3784 PART 20 Frontiers

seen as intractable, even the most effective drugs will not work if physicians fail to prescribe them and if patients fail to take them. Although

the dominant forms of investigation in medicine seek cellular or

molecular therapeutic targets to modify disease, behavioral sciences

have revealed cognitive pathways that operate nearly as predictably as

the genetic code. The opportunity for behavioral economics to improve

health and health care delivery derives from its recognition of these

behavioral pathways and the growing empirical evidence about how to

best make use of them.

■ FURTHER READING

Asch DA et al: Automated hovering in health care—Watching over the

5000 hours. N Engl J Med 367:1, 2012.

Asch DA et al: Asymmetric thinking about return on investment.

N Engl J Med 374:606, 2016.

Asch DA et al: Toward facilitated self-service in health care. N Engl J

Med 380:1891, 2019.

Connolly T, Butler DU: Regret in economic and psychological

theories of choice. J Behav Decis Mak 19:148, 2006.

John LK et al: The effect of cost sharing on an employee weight loss

program: A randomized trial. Am J Health Promot 32:170, 2018.

Kahneman D: Thinking, Fast and Slow. New York, Farrar, Straus and

Giroux, 2011.

Kahneman D, Tversky A: Prospect theory: An analysis of decision

under risk. Econometrica 47:263, 1979.

Loewenstein G, Chater, N: Putting nudges into perspective.

Behavioural Public Policy 1:26, 2017.

Loewenstein G et al: Asymmetric paternalism to improve health

behaviors. JAMA 298:2415, 2007.

Loewenstein G et al: Behavioral economics holds potential to deliver

better results for patients, insurers, and employers. Health Aff

(Millwood) 32:1244, 2013.

Patel MS et al: Generic medication prescription rates after health

system-wide redesign of default options within the electronic health

record. JAMA Intern Med 176:847, 2016.

Thaler RH, Sunstein CR: Nudge: Improving Decisions About Health,

Wealth and Happiness. New York, Penguin Books, 2008.

Volpp KG et al: Financial incentive-based approaches for weight loss:

A randomized trial. JAMA 300:2631, 2008.

Volpp KG et al: Assessing value in health care programs. JAMA

307:2153, 2012.

The search for health and improved well-being includes many treatments, practices, and systems of care that may have originated outside

conventional medicine but are gradually being folded into mainstream

health care. The current health care system is fragmented, often

emphasizing the pharmacologic treatment of disease alone, while often

neglecting the promotion, support, and, importantly, restoration of

health. Though the disease-focused model is dominant in our research

and health care ecosystem, there has been a longstanding awareness that

many chronic diseases, including pain conditions, can be prevented or

better managed by incorporating nonpharmacologic interventions such

as nutrition, exercise, and stress management into care, with an emphasis on understanding the person as a whole. Many complementary practices follow this model, and there is preliminary evidence indicating that

these approaches lead to improved self-care, a better personal sense of

482 Complementary and

Integrative Therapies

and Practices

Helene M. Langevin

well-being, and a greater commitment to a healthy lifestyle. Integrative

health emphasizes not only the integration of complementary and conventional care but also an integrative approach to treatment of the whole

person. This includes expanding our understanding of how physiologic

systems interact with one another and of the connections between

physical, psychological, and social aspects of health. Integrative health

also includes striving for a better understanding of “salutogenesis” or

pathogenesis in reverse, meaning the process by which health is restored

when recovering from an injury, acute illness, or the exacerbation of a

chronic disease, or when a “predisease” condition such as prediabetes

or prehypertension is reversed through changes in behavior rather than

pharmacologic treatment.

DEFINITIONS AND SCOPE

Complementary health therapies and practices include a broad range

of practices, interventions, and natural products that are not typically

part of conventional medical care (Table 482-1). The term complementary refers to the use of these practices together with conventional

therapies and is increasingly preferred to the term alternative, which

denotes usage as a substitute for standard care.

The term integrative health care refers to conventional and complementary therapies and practices used together in a coordinated way.

Integrative health also emphasizes care of the whole person that aims

to improve health in multiple interconnected domains: social, psychological, and physical, including multiple organs and systems.

The use of integrative approaches to health and wellness has grown

within care settings across the United States. Researchers are currently

exploring the potential benefits of integrative health in a variety of situations, including pain management for military personnel and veterans, relief of symptoms in cancer patients and survivors, and programs

to promote healthy behaviors.

Although complementary therapies and practices vary widely, it is

useful to classify them by their primary therapeutic input, which may be

dietary (e.g., diet, herbs), psychological (e.g., meditation), physical (e.g.,

massage, acupuncture), or the combination of psychological and physical

(e.g., yoga, tai chi). Although some complementary health practices are

recommended or provided by a physician or a complementary health

care provider such as a chiropractor, acupuncturist, or naturopathic

practitioner, many of these practices are undertaken as “self-care.”

Although some are reimbursed, most are paid for out of pocket.

PATTERNS OF USE

The first large survey of use of complementary health practices was

performed by David Eisenberg and associates in 1993. It surprised

the medical community by showing that >30% of Americans use

complementary health products and practices. Many surveys since that

time have extended those conclusions. The National Health Interview

Survey (NHIS), a large, national household survey in which thousands

of Americans are interviewed about their health- and illness-related

experiences, is conducted annually by the National Center for Health

Statistics, a component of the Centers for Disease Control and Prevention. This survey, which addressed the use of complementary health

practices in 2002, 2007, 2012, and 2017, uses methods that create a

nationally representative sample and has a sample size large enough

to permit valid estimates about some subgroups. Information was

obtained from 34,500 adults and 10,200 children in 2012 and 61,267

adults in 2017.*

In the first three surveys, approximately one-third of adults reported

using some form of complementary therapy or health practice. In the

2012 survey, 32.2% of adults and 11.6% of children had used one or

more modalities. These surveys yielded the estimate that nonvitamin,

nonmineral dietary supplements are used by ~18% of adults and 5% of

children. To identify trends in Americans’ use of specific practices, the

2017 survey data were compared with a version of the survey fielded

*

Information on the use of complementary health approaches was collected

from a sample of adults aged 18 and over who participated in the 2012 (n =

34,525) and 2017 (n = 26,742) NHIS of adult alternative medicine or complementary health supplements, respectively.

3785Complementary and Integrative Therapies and Practices CHAPTER 482

TABLE 482-1 Glossary of Complementary and Integrative Health Therapies and Practices

Acupuncture A family of procedures involving stimulation of defined anatomic points, a component of the major Asian medical traditions; most common

application involves penetrating the skin with thin, solid, metallic needles that are manipulated by the hands or by electrical stimulation

Ayurvedic medicine The major East Indian traditional medicine system; treatment combines products (mainly derived from plants, but may also include animal,

metal, and mineral), diet, exercise, and lifestyle

Biofeedback The use of electronic devices to help people learn to consciously control body functions such as breathing or heart rate

Chiropractic Chiropractic care involves the adjustment of the spine and joints to influence the body’s nervous system and natural defense mechanisms to

alleviate pain and improve general health; primarily used to treat back problems, headaches, nerve inflammation, muscle spasms, and other

injuries and traumas

Dietary supplement A product that is intended to supplement the diet, is taken by mouth, contains one or more dietary ingredients (including vitamins, minerals,

herbs, amino acids, or certain other substances), and is labeled as being a dietary supplement

Homeopathy A medical system with origins in Germany that is based on a core belief in the theory of “like cures like”—compounds that produce certain

syndromes, if administered in very diluted solutions, will be curative

Hypnosis The induction of an altered state of consciousness characterized by increased responsiveness to suggestion

Massage Manual therapies that manipulate muscle and connective tissues to enhance the function of those tissues and promote muscle relaxation and

well-being

Meditation A group of practices, largely based in Eastern spiritual traditions, intended to focus or control attention and obtain greater awareness of the

present moment, or mindfulness

Mind and body practices A large and diverse group of procedures or techniques that are administered or taught by a trained practitioner or teacher; examples include

acupuncture, massage therapy, meditation, relaxation techniques, spinal manipulation, tai chi, and yoga

Natural products A variety of products such as herbs (also known as botanicals), vitamins and minerals, and probiotics, which are widely marketed, readily

available to consumers, and often sold as dietary supplements

Naturopathy A clinical discipline that emphasizes a holistic approach to the patient, herbal medications, diet, and exercise; practitioners have degrees as

doctors of naturopathy

Osteopathy A clinical discipline, now incorporated into mainstream medicine, that historically emphasized spinal manipulative techniques to relieve pain,

restore function, and promote overall health

Relaxation techniques A number of practices such as progressive relaxation, guided imagery, biofeedback, self-hypnosis, and deep breathing exercises, with the

goal of producing the body’s natural relaxation response, characterized by slower breathing, lower blood pressure, and a feeling of increased

well-being

Spinal manipulation,

osteopathic manipulation

A technique where practitioners use their hands or a device to apply a controlled thrust (i.e., a force of a specific magnitude or degree in a

specific direction) to a joint of the spine

Tai chi A mind and body practice originating in China that involves slow, gentle movements and sometimes is described as “moving meditation”

Traditional Chinese

medicine

A medical system that uses acupuncture, herbal mixtures, massage, exercise, and diet

in 2012. Yoga was the most commonly used complementary health

approach among U.S. adults in 2012 (9.5%) and 2017 (14.3%). The

use of meditation increased more than threefold from 4.1% in 2012 to

14.2% in 2017. The percentage of children aged 4–17 years who used

yoga in the previous 12 months increased significantly from 3.1% in

2012 to 8.4% in 2017. Meditation increased significantly from 0.6% in

2012 to 5.4% in 2017.

Americans are willing to pay for complementary health products

and practices; the estimated out-of-pocket expenditure for complementary health practices in 2012 was $30.2 billion ($28.3 billion for

adults and $1.9 billion for children), representing 1.1% of total health

expenditures and 9.2% of out-of-pocket costs. On visits to complementary practitioners, Americans spent $14.7 billion out of pocket, which

is almost 30% of what they spent out of pocket on services by conventional physicians ($49.6 billion). On natural products, such as dietary

supplements, Americans spent $12.8 billion out of pocket, which was

about one-quarter (24%) of what they spent out of pocket on prescription drugs ($54.1 billion).

According to the NHIS surveys, painful conditions are the most

common reasons why American adults use complementary health

products and practices. About 40 million American adults experience severe pain in any given year, and they spend >$14 billion

out of pocket on complementary therapies to manage their pain.

In one analysis of data from the 2012 NHIS survey, >40% of people

with a musculoskeletal pain disorder used a complementary health

approach. This was significantly higher than use by people without

a musculoskeletal pain disorder (24%). Many complementary and

integrative health interventions are multimodal in nature and may

contribute to pain relief by impacting several pain processes simultaneously and addressing the cognitive, emotional, and physical

complexities associated with pain.

Some patients seek out complementary health practitioners

because they offer optimism or greater personal attention. For others,

therapies and practices perceived as outside the mainstream reflect a

“self-help” approach to health and wellness or satisfy a search for “natural” or less invasive alternatives. Since dietary supplements are labeled

as “natural,” they are often believed, incorrectly, to be inherently healthy.

CATEGORIES OF COMPLEMENTARY

AND INTEGRATIVE HEALTH THERAPIES

AND PRACTICES BASED ON PRIMARY

THERAPEUTIC INPUT

■ PRIMARY DIETARY INPUT

Natural products, including plant and animal products, have a long and

impressive history as sources of medicine and as important resources

for biologic research. Whether as herbal supplements or as part of a diet,

natural products are frequently consumed as a complex mixture. This

complexity is further amplified by potential interactions with endogenous metabolic pathways, including those associated with the microbiome. The result is a collection of natural products and their metabolites

that, individually and/or collectively, are associated with a network of

biologic activity. Importantly, in addition to direct action on biologic

targets, the activity of natural products can be influenced by an individual’s health and metagenomic background. Although much remains to

be understood about mechanisms of action, results of research on some

natural products for a few conditions appear promising.

Pain Recent research to identify new sources of medicine based on

natural products has yielded beneficial tools for probing the molecular

features of pain pathways. Since the early days of pharmacology, natural products such as the opium poppy and capsaicin have provided

3786 PART 20 Frontiers

important insights into the molecular basis of pain sensation. Coupled

with human genetics, preclinical animal models, and clinical pharmacology, natural product research is continuing to help validate new

targets for pain relief. Resiniferatoxin (RTX), produced by euphorbias,

is effective as a long-duration, nonopioid, single-administration treatment for bone cancer pain. In recent laboratory studies, conolidine,

derived from Tabernaemontana divaricata, appears to have analgesic

properties; however, its mechanism of action remains unclear. Two

compounds in kratom (Mitragyna speciosa) leaves, mitragynine and

7-hydroxymitragynine, interact with opioid receptors in the brain,

decreasing pain when taken in high doses; however, to date, there are

no clinical trials to evaluate the health effects of kratom or to determine if kratom is an effective or safe treatment for any pain condition

or for opioid addiction. Other research is examining the potentially

valuable effects of botulinum toxin, asymptomatic bacteriuria (ASB)

strains of Escherichia coli, snail venom, and the vitamin B isoform

nicotinamide riboside on pain. There is also some evidence that

devil’s claw (Harpagophytum procumbens) may be helpful for low-back

pain over the short term. An increasing amount of attention has been

given recently to the nonpsychogenic effects of cannabinoids, such

as cannabidiol (CBD), and terpenes found in the cannabis plant on

chronic pain, particularly neuropathic pain; studies have found low- to

moderate-quality evidence that these medicines produced better pain

relief than placebos.

Anxiety Some research suggests that a chamomile extract may be

helpful for generalized anxiety disorder, but the studies are preliminary,

and their findings are not conclusive. Melatonin may help reduce anxiety in patients who are about to have surgery and may be as effective as

standard treatment with midazolam in reducing preoperative anxiety.

Rheumatoid Arthritis Clinical trials on rheumatoid arthritis (RA)

have found that fish oil supplements can help alleviate tender joints and

morning stiffness and reduce the daily nonsteroidal anti-inflammatory

drug (NSAID) requirement of RA patients. Gamma-linolenic acid

(GLA) is an omega-6 fatty acid found in the oils from some plants,

including evening primrose (Oenothera biennis), borage (Borago officinalis), and black currant (Ribes nigrum). Oils containing GLA may

have some benefit in relieving RA symptoms; however, only a few

studies have been conducted on each of the oils. Thunder god vine

(Tripterygium wilfordii), an herb used in traditional Chinese medicine,

may improve some RA symptoms, but there have been only a few

high-quality studies for this condition.

Irritable Bowel Syndrome There is some evidence that entericcoated peppermint oil capsules are modestly efficacious, in the

short-term, in reducing several common symptoms of irritable bowel

syndrome (IBS), in particular abdominal pain, bloating, and gas.

Long-term efficacy has not been established. Probiotics may improve

symptoms of IBS; however, benefits have not been conclusively demonstrated, and not all probiotics have the same effects.

Depression At present, it is uncertain whether omega-3 fatty acid

supplementation is useful for depression. Some studies have shown

small effects in adjunctive therapy in patients with a diagnosis of major

depressive disorder (MDD) and in depressive patients without a diagnosis of MDD; however, most trials have been adjunctive studies. Controlled trials of omega-3 fatty acids as monotherapy are inconclusive

compared to standard antidepressant medicines, and it remains unclear

whether a mechanism is present to suggest that a pharmacologic or

biologic antidepressant effect exists. Results of some studies suggest

that St. John’s wort (Hypericum perforatum) may have an effect on mild

to moderate MDD for a limited number of patients, similar to standard

antidepressants, but the evidence is far from definitive. Although some

studies have demonstrated a slight efficacy over placebo, others contradict these findings.

Smoking Cessation The natural product cytisine, primarily used

in Central and Eastern European countries for smoking cessation, is

not currently approved by the U.S. Food and Drug Administration

(FDA) but is undergoing testing in the United States.

Eye Disease Findings from the Age-Related Eye Disease Studies

(AREDS and AREDS2) suggest that dietary supplementation with

antioxidant vitamins and zinc may slow the progression of age-related

macular degeneration (AMD) in people who have intermediate AMD

and those who have late AMD in one eye. The AREDS2 trial found

that adding lutein and zeaxanthin or omega-3 fatty acids to the original

AREDS formulation (with beta-carotene) had no overall effect on the

risk of late AMD. However, the trial also found that replacing betacarotene with a 5-to-1 mixture of lutein and zeaxanthin helped further

reduce the risk of late AMD.

Multiple Sclerosis Orally administered cannabinoids (cannabis

extract, synthetic tetrahydrocannabinol [THC]), mucosally delivered

cannabinoids (cannabis THC and CBD extract oral spray, nabiximols

[trade name Sativex]), and smoked cannabis have all been studied for

therapeutic effects in multiple sclerosis (MS). Based on available evidence, cannabinoids may relieve spasticity and/or pain in people with

MS; however, no marijuana-derived medications are approved by the

FDA to treat MS. Sativex, an oral mucosal spray containing a mixture of

THC and CBD, has received regulatory approval in >25 countries outside the United States for the treatment of spasticity (muscle stiffness/

spasm) due to MS. Sativex is currently licensed in the United Kingdom

for use as an add-on treatment for MS-related spasticity when people

have shown inadequate response to other symptomatic treatments.

Importantly, the psychoactive properties and other potential adverse

effects of preparations containing cannabinoids need to be considered,

including interactions with other medications and natural products;

more research is needed in this area.

Other Conditions There has been limited research on various

natural products for several other conditions such as attention-deficit/

hyperactivity disorder, hypercholesterolemia, seasonal affective disorder, and psoriasis, but no definitive conclusions about efficacy can be

drawn.

General Health and Wellness In the 2012 NHIS, users of natural

product supplements were twice as likely to report taking the natural

product for a wellness reason than for treatment of a specific health

condition (88.9 vs 44.9%, respectively). Although to date, research on

natural products has focused on their use for specific diseases as outlined above, a better understanding is needed about how natural products, including food, can be used most effectively to support health.

Challenges One challenge in this area is the extremely varied doses

of natural products that are sold over the counter and used without

much guidance or evidence of efficacy. We also know from research on

vitamins that “more is not necessarily better” and that taking a “natural” substance such as a vitamin in quantities that greatly exceed what

is found in food can be harmful.

Additional challenges in the assessment of plant products include

their complexity and variability, including possible instability of active

components or the presence of impurities, conflicting or unreliable

conclusions in the literature, and low statistical power of studies. Further, there is a paucity of data on the safety of many products, including

the safety of their use in a twenty first century context (e.g., if taken

with modern prescription drugs) and their appropriate use in the context of traditional or indigenous practices.

Regulation There is an important distinction between natural

products sold as dietary supplements and drugs developed from

natural sources that are used to treat specific diseases. The Dietary

Supplement Health and Education Act (DSHEA), passed in 1994,

gives authority to the FDA to regulate dietary supplements, but with

expectations that differ in many respects from the regulation of drugs

or food additives. Purveyors of dietary supplements cannot claim

that they prevent or treat any disease. They can, however, claim that

they maintain “normal structure and function” of body systems. For

example, a product cannot claim to treat arthritis, but it can claim to

maintain “normal joint health.”

Homeopathic products predate FDA drug regulations and are

sold with no requirement that they be proved effective. Although

3787Complementary and Integrative Therapies and Practices CHAPTER 482

homeopathic products are widely believed to be safe because they are

highly dilute, one product, a nasal spray called Zicam, was withdrawn

from the market when it was found to produce anosmia, probably

because of significant zinc content. In January 2017, the FDA warned

consumers about homeopathic teething tablets containing belladonna

that pose a serious risk to infants and children.

Regulation of advertising and marketing claims is the purview of

the Federal Trade Commission (FTC). The FTC does take legal action

against promoters or websites that advertise or sell dietary supplements

with false or deceptive statements. Misleading marketing of dietary

supplements, homeopathic products, and indeed other complementary

health products and practices contributes to the very significant risk

that individuals will use them instead of effective conventional modalities. For example, in April 2020, the FTC sent warning letters to several

companies allegedly selling unapproved products—some of which

included high-dose dietary supplements—that may violate federal law

by making deceptive or scientifically unsupported claims about their

ability to treat or cure COVID-19.

Inherent Toxicity Although the public may believe that “natural”

equates with “safe,” it is abundantly clear that natural products can

be toxic. Misidentification of medicinal mushrooms has led to liver

failure. Contamination of tryptophan supplements caused the eosinophilia-myalgia syndrome. Herbal products containing particular

species of Aristolochia were associated with genitourinary malignancies

and interstitial nephritis. In 2013, dietary supplements containing

1,3-dimethylamylamine (DMAA), often touted as a “natural” stimulant, led to cardiovascular problems, including heart attacks. Among

the most controversial dietary supplements is Ephedra sinica, or ma

huang, a product used in traditional Chinese medicine for short-term

treatment of asthma and bronchial congestion. The scientific basis for

these indications was revealed when ephedra was shown to contain

ephedrine alkaloids, especially ephedrine and pseudoephedrine. With

the promulgation of the DSHEA regulations, supplements containing

ephedra and herbs rich in caffeine sold widely in the U.S. marketplace

because of their claims to promote weight loss and enhance athletic

performance. Reports of severe and fatal adverse events associated with

use of ephedra-containing products led to an evidence-based review of

the data surrounding them, and in 2004, the FDA banned their sale in

the United States.

A major current concern with dietary supplements is adulteration

with pharmacologically active compounds. Multi-ingredient products

marketed for weight loss, bodybuilding, “sexual health,” and athletic

performance are of particular concern. Recent FDA recalls have

involved contamination with steroids, diuretics, stimulants, and phosphodiesterase type 5 inhibitors.

Herb-Drug Interactions A number of natural products have

potential impacts on the metabolism of drugs. This effect was illustrated

most compellingly with the demonstration in 2000 that consumption

of St. John’s wort interferes with the bioavailability of the HIV protease

inhibitor indinavir. Later studies showed its similar interference with

metabolism of topoisomerase inhibitors such as irinotecan, with cyclosporine, and with many other drugs. The breadth of interference stems

from the ability of hyperforin in St. John’s wort to upregulate expression

of the pregnane X receptor, a promiscuous nuclear regulatory factor that

promotes the expression of many hepatic oxidative, conjugative, and

efflux enzymes involved in drug and food metabolism.

Because of the large number of compounds that alter drug metabolism and the large number of agents some patients are taking, identification of all potential interactions can be a daunting task. Several useful

Web resources are available as information sources (Table 482-2).

Clearly, attention to this problem is particularly important with drugs

with a narrow therapeutic index, such as anticoagulants, antiseizure

medications, antibiotics, immunosuppressants, and cancer chemotherapeutic agents. Although there are many examples of substances of

natural origin successfully used as pharmaceutical drugs, in general,

natural products ingested as food, rather than concentrated extracts,

are less likely to cause harm.

■ PRIMARY PSYCHOLOGICAL AND PHYSICAL INPUT

“Mind and body” practices and disciplines consist of physical procedures or exercises, manual therapies, or mental techniques that

are administered or taught by a clinician, trained practitioner, or

teacher. Examples include acupuncture, massage therapy, meditation,

relaxation techniques, spinal manipulation, and yoga. These practices

are being used with increasing frequency in mainstream health care

facilities for both patients and health care providers. The evidence

base for the effectiveness of mind and body practices is still relatively

incomplete, but a few rigorous examples where there is promise of usefulness and safety include acupuncture and tai chi for pain associated

with osteoarthritis (OA) of the knee; tai chi for fibromyalgia; mindfulness meditation for anxiety-related symptoms; relaxation techniques

for acute stress disorder or posttraumatic stress disorder (PTSD) and

headaches and migraine; yoga for fatigue and sleep disturbances,

depression and anxiety, and quality of life of breast cancer patients;

and acupuncture, massage, yoga, and spinal manipulation for chronic

back pain. New research is shedding light on the effects of meditation

and acupuncture on central mechanisms of pain processing and perception and the regulation of emotion and attention. Although many

unanswered questions remain about these effects, findings are pointing

to scientifically plausible mechanisms by which these modalities might

yield benefit.

Primary Psychological Input For some mind and body therapies and practices, the primary therapeutic input is predominantly

mental. This category includes conventional types of psychotherapy,

such as cognitive behavioral therapy (CBT), and complementary

practices, such as meditation and mindfulness-based stress reduction

(MBSR). Relaxation techniques, including biofeedback-assisted relaxation, also fall into this category. The boundary between conventional

and complementary can be blurred, as CBT programs, for example,

frequently incorporate elements of MBSR and relaxation techniques.

These therapies and practices are being gradually integrated into

aspects of conventional care, such as cardiac rehabilitation programs,

and are playing an increasingly recognized role in the management of

pain, as well as stress and sleep disturbances.

PAIN Mindfulness meditation has been found to significantly reduce

pain in experimental and clinical settings and to improve a wide

spectrum of clinically relevant cognitive and health outcomes, including for low-back pain and fibromyalgia. It is unclear if the analgesic

mechanisms supporting mindfulness meditation are distinct from or

parallel to those engaged by placebo and/or slow, rhythmic breathing;

however, there is emerging evidence suggesting that mindfulness

meditation engages multiple unique neural mechanisms not mediated

by endogenous opioids to reduce pain. In addition, findings from

a few studies have demonstrated that training patients in the use

of self-hypnosis significantly reduced their need for sedatives and

TABLE 482-2 Resources for Dietary Supplement–Drug Interactions

National Institutes of Health National Center for Complementary and

Integrative Health (NCCIH)

https://www.nccih.nih.gov/health/know-science/how-medications-supplements-interact

The National Institutes of Health NCCIH Know the Science initiative provides

information for patients about complex scientific health topics such as drugsupplement interactions.

Medscape

http://www.medscape.com/druginfo/druginterchecker?cid=med

This website is maintained by WebMD and includes a free drug interaction

checker tool that provides information on interactions between two or more

drugs, herbals, and/or dietary supplements.

Natural Medicines

https://naturalmedicines.therapeuticresearch.com/tools/interaction-checker.aspx

This website provides an interactive natural product–drug interaction checker

tool that identifies interactions between drugs and natural products, including

herbals and dietary supplements. This service is available by subscription.

3788 PART 20 Frontiers

analgesia when undergoing interventional radiologic procedures. The

efficacy of biofeedback has been evaluated in numerous studies for

tension headaches, with positive results. Several studies have shown

that biofeedback decreased the frequency of both pediatric and

adult migraines, with some showing an effect lasting over an average

follow-up phase of 17 months.

SLEEP DISORDERS The American College of Physicians practice

guidelines (2016) strongly recommend the use of CBT for insomnia

(also called CBT-I) as the initial treatment for chronic insomnia.

Although CBT-I often includes relaxation techniques, it is not clear

whether relaxation alone is beneficial.

ANXIETY AND STRESS-RELATED DISORDERS Meditation therapy is

commonly used and has been shown to be of small to modest benefit

for people with anxiety-related symptoms. There is some evidence

that transcendental meditation may have a beneficial effect on anxiety.

However, there is a lack of studies with adequate statistical power in

patients with clinically diagnosed anxiety disorders, which makes it difficult to draw firm conclusions about its efficacy in this context. Relaxation techniques may be helpful in managing a variety of stress-related

health conditions, including anxiety associated with ongoing health

problems and in those who are having medical procedures. Some studies also have suggested that hypnosis may be helpful for anxiety and

health-related quality of life in people with IBS. Evidence suggests that

relaxation techniques may also provide some benefit for symptoms of

PTSD and may help reduce occupational stress in health care workers.

For some of these conditions, relaxation techniques are used as an

adjunct to other forms of treatment.

MENOPAUSAL SYMPTOMS There is some evidence suggesting that

hypnosis may help improve certain menopausal symptoms, such as

hot flashes.

SUBSTANCE USE DISORDERS There is some evidence to suggest

that hypnotherapy may improve smoking cessation, but data are not

definitive. Available data suggest that mindfulness-based interventions may help significantly reduce the consumption of several substances including alcohol, cigarettes, opiates, and others compared to

control groups; however, many studies have had small sample sizes,

methodologic problems, and a lack of consistently replicated findings.

Primary Physical Input For another group of mind and body

interventions, the primary therapeutic input is predominantly physical.

The physical input can be delivered manually (e.g., massage) or using

a device (e.g., acupuncture) or can be generated by the patient (e.g.,

exercise).

PAIN The role of acupuncture in pain management has been controversial for decades, with critics pointing out its “prescientific”

theoretical basis, and indeed, the rationale for the use of specific “acupuncture points” remains to be established. However, recent large-scale

meta-analyses have demonstrated acupuncture to be superior to both

usual care and sham acupuncture for chronic musculoskeletal pain,

headache, and OA, with beneficial treatment effects persisting for up

to 12 months. The most recent (2017) American College of Physicians

clinical guidelines recommend acupuncture as one of the initial treatment options for patients with acute, subacute, and chronic low-back

pain. The role of both osteopathic and chiropractic spinal manipulative

therapies (SMTs) in management of low-back pain also has been the

subject of a number of carefully performed trials and many systematic

reviews. Conclusions are not consistent, but the American College of

Physicians guidelines conclude that spinal manipulation has a small

effect on improving function and pain compared with control—either

a sham manipulation or an inert treatment. Although evidence for

spinal manipulation for chronic low-back pain is graded as low quality,

the recommendation for consideration of nonpharmacologic treatment

including spinal manipulation is graded as a strong recommendation,

reflecting increasing concern with the impact of chronic opioid use

for low-back pain. The evidence of benefit of spinal manipulation

for neck pain is not as extensive, and continued concern that cervical

manipulation may occasionally precipitate vascular injury clouds a

contentious debate. Low- to moderate-quality evidence suggests that

massage therapy is superior to nonactive therapies in reducing arthritis

pain and improving functional outcomes. Massage may provide shortterm relief from low-back pain, but the evidence is not of high quality.

There is some evidence that massage has a positive effect on migraine,

tension headaches, and neck pain.

DEPRESSION Acupuncture may provide a modest reduction in symptoms of depression, particularly when compared with no treatment or

a control.

CANCER SYMPTOMS AND TREATMENT SIDE EFFECTS Acupuncture or

electroacupuncture may be an appropriate addition to drug treatment

for managing treatment-related nausea and vomiting in patients with

cancer.

SEASONAL ALLERGIES Acupuncture may relieve symptoms of allergic

rhinitis. Clinical practice guidelines from the American Academy of

Otolaryngology–Head and Neck Surgery include acupuncture among

the options that health care providers may offer to interested patients

with allergic rhinitis.

Combined Psychological and Physical Input The primary

therapeutic input for other mind and body practices is a combination

of physical and psychological. Examples of practices in this category

include yoga and tai chi, which combine movement, physical postures,

and meditation.

PAIN Yoga and tai chi can be beneficial for patients with fibromyalgia

or chronic low-back pain, and yoga compared to nonexercise controls

results in small to moderate improvements in back-related function at

3 and 6 months. Some studies have demonstrated that tai chi produces

beneficial effects similar to those of standard physical therapy in the

treatment of knee OA. Regular yoga training may be helpful in reducing knee arthritis symptoms in patients with OA or RA.

MOTOR FUNCTION Tai chi has been shown to improve overall motor

function, including balance and stability in older adults.

GENERAL WELLNESS Yoga may benefit people’s general wellness by

relieving stress, supporting good health habits, and improving mental/

emotional health and sleep. Yoga may also help with quitting smoking,

anxiety or depressive symptoms associated with difficult life situations,

and quality of life for people with chronic diseases. Tai chi also may also

improve quality of life in people with heart disease, cancer, and other

chronic illnesses.

MULTIMODAL THERAPIES AND SYSTEMS

Multimodal approaches to health comprise two or more interventions

such as conventional medicine, lifestyle changes, physical rehabilitation, psychology, and complementary health practices in various

combinations, with an emphasis on whole-person health. Complementary health therapies and practices are often multimodal in nature,

both in traditional health systems (e.g., traditional Chinese medicine,

naturopathy) and in modern integrative practice. The U.S. Veterans

Health Administration uses a multimodal model of pain care that

emphasizes nonpharmacologic methods, both conventional (e.g.,

physical therapy, CBT) and complementary (e.g., yoga, acupuncture),

and may also include nutrition consultations. Several medical systems,

such as chiropractic, osteopathy, naturopathy, and homeopathy, that

arose in the late nineteenth century continue to be practiced today.

Osteopathic medicine is mostly integrated into conventional medicine,

while homeopathy and naturopathy have remained largely separate

from mainstream medicine. Chiropractic care is increasingly available

in some conventional care settings. A number of multimodal systems,

often called “whole health” systems, such as traditional Chinese medicine, Ayurveda, and homeopathy, use a diagnostic and therapeutic

framework that is different from that of conventional medicine, which

has posed additional challenges to their rigorous investigation.

■ NATUROPATHY

Naturopathy, or naturopathic medicine, is a multimodal therapeutic system based on philosophical principles that guide practice.

3789Complementary and Integrative Therapies and Practices CHAPTER 482

Naturopaths prescribe conventional and unconventional diagnostic

tests and medications, with an emphasis on relatively low doses of

drugs, herbal medicines, healthy diet, and exercise.

■ CHIROPRACTIC

The practice of chiropractic care, founded by David Palmer in 1895, is

the most widespread practitioner-based complementary health practice in the United States. Although the scope of practice varies widely,

chiropractic practice emphasizes manual therapies for treatment of

musculoskeletal complaints.

■ OSTEOPATHIC MEDICINE

Founded in 1892 by the physician Andrew Taylor Still, osteopathic

medicine was originally based on the belief that manipulation of soft

tissue and bone can correct a wide range of diseases of the musculoskeletal and other organ systems. Over the ensuing century, the osteopathic

profession has welcomed increasing integration with conventional

medicine. Today, the postgraduate training, practice, credentialing, and

licensure of osteopathic physicians are virtually indistinguishable from

those of allopathic physicians. Osteopathic medical schools, however,

include training in manual therapies, particularly spinal manipulation,

as well as diagnostic methods based on palpation of musculoskeletal

tissues that are not part of conventional medical education.

■ HOMEOPATHY

The theoretical framework of homeopathy is based on two unconventional principles: “like cures like,” the notion that a disease can

be cured by a substance that produces similar symptoms in healthy

people; and the “law of minimum dose,” the notion that the lower the

dose of the medication, the greater its effectiveness. Although the current lack of biologic underpinning for these principles has seriously

limited the rationale for their use, the diagnostic framework of homeopathy could be the source of new insights that could be explored.

As discussed previously, the regulatory framework for homeopathic

remedies differs from that for dietary supplements. Homeopathic

remedies are widely available and commonly recommended by naturopathic physicians, chiropractors, and other licensed and unlicensed

practitioners.

■ RESEARCH CHALLENGES

Classic randomized controlled trial (RCT) designs may not be well

suited for research on multimodal complementary interventions and

systems such as naturopathy and Ayurvedic medicine. The dynamic

relationships among an array of factors that affect health and wellness

is inherent to the philosophy of these systems of care and poses methodologic challenges to the effective application of conventional RCT

design. Pragmatic comparative effectiveness designs with “usual care”

comparators are widely used to study these types of interventions, and

trials may need to take into account the individualization of interventions and the underlying theories of these multimodal systems. Thus,

a key component of research on multimodal therapeutic systems is the

development of validated and reproducible “manualized” treatment

protocols allowing for some flexibility and individual patient care.

Pragmatic studies that compare multimodal treatments with usual

care cannot determine which treatment components are responsible

for benefits, but other kinds of translational studies can address this

issue.

THERAPEUTIC OUTPUT—SYSTEMS

IMPACTED AND CHALLENGES OF

MECHANISTIC RESEARCH

Complementary and integrative interventions whose therapeutic input

is dietary, psychological, and/or physical may exert their effects, or

therapeutic output, through a variety of mechanisms and physiologic

systems. For example, peppermint oil may relieve pain associated with

IBS by directly relaxing gastrointestinal smooth muscle, probiotics

may have effects on the nervous system as well as the gut, and some

components of traditional Chinese medicine, as well as omega-3 fatty

acids and their derivatives, have immune-mediated anti-inflammatory

effects. Multimodal interventions with psychological and/or physical

therapeutic input such as meditation and acupuncture can have effects

on the nervous system and may also target other body systems affected

by the pain condition; for example, tai chi may improve balance and

stability by increasing flexibility and core strength, and the stretching

involved in yoga may improve low-back pain by reducing connective

tissue inflammation. For all types of therapeutic input, biopsychosocial

interactions also may be important; for example, participation in an

integrative group therapy pain management program may provide

tools to help relieve symptoms of anxiety and depression as well as

pain.

Deepening the scientific understanding of the connections that exist

across domains of human health is important to better understand

how conditions interrelate, identify multimodal interventions that

address these problems, and increase the support of patients through

the full continuum of their health experience, including the return to

health. Studies of multimodal interventions often require multidisciplinary expertise and use state-of-the-art techniques in areas such as

neuroscience, immunology, pharmacognosy, proteomics, genetics, and

epigenomics. Further, there are limited preclinical models for some

complementary health interventions (e.g., no relevant model for meditative movement practices such as yoga or tai chi). Objective, validated

measurement tools are essential, as are processes and procedures to

ensure quality control, whether the intervention is a mind and body

practice or a natural product.

PATIENT AND PROVIDER RESOURCES

Physicians regularly face difficult challenges in providing patients

with advice and education about complementary health therapies

and practices. Of particular concern to all physicians are practices of

uncertain safety and practices that raise inappropriate hopes. Cancer

therapies, antiaging regimens, weight-loss programs, and products

that claim to improve sexual function or athletic performance are

frequently targeted for excessive claims and irresponsible marketing.

A number of Internet resources provide critical tools for patient education (Table 482-3). Because many complementary health products

TABLE 482-3 Internet Resources on Complementary Health Approaches

The Cochrane Collaboration Complementary Medicine Reviews

This website offers rigorous systematic reviews of mainstream and

complementary health interventions using standardized methods. It includes

>300 reviews of complementary health practices. Complete reviews require

institutional or individual subscription, but summaries are available to the public.

http://www.cochrane.org/evidence

MedlinePlus All Herbs and Supplements, A–Z List

MedlinePlus Complementary and Integrative Medicine

MedlinePlus Dietary Supplements

These National Library of Medicine (NLM) Web pages provide an A–Z database

of science-based information on herbal and dietary supplements; basic facts

about complementary and integrative health practices; and federal government

sources on information about using natural products, dietary supplements,

medicinal plants, and other complementary health modalities.

http://www.nlm.nih.gov/medlineplus/druginfo/herb_All.html

https://medlineplus.gov/complementaryandintegrativemedicine.html

http://www.nlm.nih.gov/medlineplus/dietarysupplements.html

National Institutes of Health National Center for Complementary and

Integrative Health (NCCIH)

This National Institutes of Health NCCIH website contains information for

consumers and health care providers on many aspects of complementary and

integrative health products and practices. Downloadable information sheets

include short summaries of complementary health approaches, uses and risks of

herbal therapies, and advice on wise use of dietary supplements.

http://www.nccih.nih.gov

Resources for Health Care Providers: http://www.nccih.nih.gov/health/providers

NCCIH Clinical Digest e-Newsletter: http://www.nccih.nih.gov/health/providers/digest

Continuing medical education lectures: http://www.nccih.nih.gov/training/videolectures

3790 PART 20 Frontiers

and practices are used as self-care and because many patients research

these interventions extensively on the Internet, directing patients to

responsible websites can often be very helpful.

The scientific evidence regarding complementary therapies is

fragmentary and incomplete. Nonetheless, in some areas, particularly

pain management, it is increasingly possible to perform the kind

of rigorous systematic reviews of complementary health therapies

and practices that are the cornerstone of evidence-based medicine.

A particularly valuable resource in this respect is the Cochrane

Collaboration, which has performed >300 systematic reviews of

complementary health practices. Practitioners will find this a valuable resource to answer patient questions. Practice guidelines,

particularly for pain management, are also available from several

professional organizations. Links to these resources are provided in

Table 482-3.

SUMMARY

The frequent use of complementary and integrative health therapies

and practices reflects an active interest among the public in improving

health and well-being of the whole person. The current health care

system is fragmented, with diseases and comorbid conditions mostly

treated separately, sometimes with drugs that interact with one another.

An important step in whole-person health care is considering health

and disease not as separate states but as a bidirectional continuum

and understanding how complementary and integrative therapies and

practices, which are often multimodal in nature, consider a patient’s

long-term recovery and overall health.

Acknowledgment

Drs. Josephine Briggs and Stephen Straus contributed to this chapter in

prior editions, and some material from prior edition chapters has been

retained here.

■ FURTHER READING

Black LI et al: Use of complementary health approaches among

children aged 4–17 years in the United States: National Health

Interview Survey, 2007-2012. National health statistics reports;

no 78. Hyattsville, MD, National Center for Health Statistics,

2015.

Eisenberg DM et al: Trends in alternative medicine use in the United

States, 1990–1997: Results of a follow-up national survey. JAMA

280:1569, 1998.

Gaston TE et al: “Natural” is not synonymous with “safe”: Toxicity

of natural products alone and in combination with pharmaceutical

agents. Regul Toxicol Pharmacol 113:104642, 2020.

Ijaz N et al: Whole systems research methods in health care: A scoping

review. J Altern Complement Med 25:S21, 2019.

Nahin RL et al: Evidence-based evaluation of complementary health

approaches for pain management in the United States. Mayo Clin

Proc 91:1292, 2016.

Nahin RL et al: Expenditures on complementary health approaches:

United States, 2012. Natl Health Stat Rep 95:1, 2016.

Paige NM et al: Association of spinal manipulative therapy with clinical benefit and harm for acute low back pain: Systematic review and

meta-analysis. JAMA 317:1451, 2017.

Qaseem A et al: Noninvasive treatments for acute, subacute, and

chronic low back pain: A clinical practice guideline from the American

College of Physicians. Ann Intern Med 166:514, 2017.

Skelly AC et al: Noninvasive nonpharmacological treatment for

chronic pain: A systematic review up-date. Comparative Effectiveness Review No. 227. AHRQ Publication No. 20-EHC009.

Rockville, MD, Agency for Healthcare Research and Quality; April

2020.

Vickers AJ et al: Acupuncture for chronic pain: Update of an individual patient data meta-analysis. J Pain 19:455, 2018.

The term epigenetics was coined by Conrad Waddington in 1942, as he

sought to explain how changes in phenotype could occur throughout

development independent of any changes to genotype. Appending

the prefix epi- (Greek, meaning “over, outside of, around”) to genetics

aptly describes the numerous mechanisms by which gene expression and phenotypes are influenced—and sometimes even inherited

through cell division—independent of any changes to the underlying

DNA sequence. Today, epigenetics occupies one of the most exciting

topics in biology and medicine, offering profound opportunities for

discovery, as well as promise for the development of new therapies for

disease. Interdisciplinary by nature, the field crosses virtually all areas

of science and medicine: chemistry and genetics, development and

differentiation, immunology, cancer, aging, and neuroscience.

The continuous introduction of ever more powerful technologies

for interrogating the epigenome has led epigenetics to become one of

the most innovative fields within the biomedical sciences. Given the

vast expanse of the topic and limitations of space, in this chapter, we

provide a broad but brief overview of the field and then highlight key

areas across the landscape of biomedicine where epigenetics has been

revealed to play critical roles in physiology and disease, and importantly, where epigenetics-based therapies have demonstrated success

in clinical medicine.

■ THE BIOCHEMICAL BASES OF EPIGENETICS

Fundamental to epigenetic regulation is the intricate organization into

chromatin of each cell’s genome (Chap. 466). The fundamental unit

of the packaging into chromatin is the nucleosome, consisting of 147

base pairs of DNA wrapped around an octamer of 8 histone proteins

(two copies of each of the four core histone proteins: H2A, H2B, H3,

and H4), and nucleosome assembly into a regular repeating spaced

array along the DNA polymer. The presence of nucleosomes and level

of compaction of this basic chromatin array determine the accessibility

of the DNA strand to transcription factors, to DNA repair machinery,

and to other DNA-binding entities. Thus, compaction has a profound

influence on gene expression levels and on local DNA mutation rates.

Open regions of chromatin (euchromatin) tend to be transcriptionally

active, whereas compacted chromatin (heterochromatin) tends to be

transcriptionally repressed. Higher order three-dimensional chromatin

architecture such as folding and looping further contribute to epigenetic gene regulation and cellular phenotypes.

Histones include the four core histones, which are the most abundant and most frequently found throughout the genome, and the variant histones of H2A, H2B, and H3. The individual protein structures of

both core and variant histones include amino- and carboxyl-terminal

“tails,” which are extended and unstructured, and highly conserved

globular domains. The x-ray crystal structure of the nucleosome particle has illuminated the dynamic alterations of chromatin by an astonishing range of regulatory mechanisms, summarized below.

The three main processes that regulate chromatin compaction, and

thus access to the DNA template, include direct methylation modifications (and oxidized derivatives of methylation) of the DNA strand

itself, posttranslational modifications of histones, and remodeling of

nucleosomes to alter their location and composition with variant histones (Fig. 483-1). The major modification of DNA is cytosine methylation of CpG dinucleotides (5-mC), associated with gene repression

and catalyzed by the DNMT1, DNMT3A, and DNMT3B enzymes.

DNMT3A and 3B catalyze the addition of methyl groups on unmethylated DNA de novo at CpG dinucleotides that are typically located

throughout transcribed genes and in intergenic regions, but lacking

at promoters, while DNMT1 is critical for the maintenance of the

483 The Role of Epigenetics

in Disease and Treatment

Brian C. Capell, Shelley L. Berger

3791The Role of Epigenetics in Disease and Treatment CHAPTER 483

including transcription, replication, DNA repair, and recombination.

One key point is that the staggering numbers of writers, erasers, and

readers provide unlimited potential for diagnostic and therapeutic

pharmacologic discovery.

Throughout this chapter, we focus on histone acetylation and

methylation, the most abundant and the most well-studied hPTMs

(Fig. 483-1), although a wealth of additional modifications, such

as serine/threonine/tyrosine phosphorylation, lysine ubiquitination,

lysine SUMOylation, and lysine ADP-ribosylation, among others,

play important roles in transcriptional and chromatin regulation.

For instance, histone phosphorylation targets histone H2A at Ser139

(γH2A.X), which marks DNA double-strand breaks immediately following DNA damage and is critical for the recruitment of the DNA

repair machinery. Histone mono-ubiquitination functions similarly

to other hPTMs, in signaling and marking the chromatin template,

in particular serving to mark the initiation region or elongation of

TCA ATP

Bone

marrow

Appendix

Histone

methylation

DNA

methylation

Histone

acetylation

Chromosome

DNA

Nucleosome

Tonsils

Thymus

Lymph nodes

Spleen

IMMUNE SYSTEM

BRAIN AND BEHAVIOR

DEVELOPMENT AGING

CANCER METABOLISM

Glucose ETC

FIGURE 483-1 Epigenetic pathways influence multiple physiologic and disease pathways. As depicted in the center of the illustration, epigenetics refers to the chemical

modifications of DNA and histones, which influence chromatin structure, gene expression, and susceptibility to mutations. These molecular pathways, in turn, play important

roles in development, cancer, metabolism, aging, neural function, and behavior, and in the immune system. ETC, electron transport chain; TCA, tricarboxylic acid.

methylation state after DNA replication and after transcription during

the S phase of the cell cycle. To further alter and to remove methylation,

the TET enzymes (TET1–3) progressively oxidize 5-methylcytosine

(5-mC) to 5-hydroxymethylcytosine (5-hmC), to 5-formylcytosine

(5-fC), and to 5-carboxylcytosine (5-caC), which are unable to be

recognized by DNMT1 but can be removed by additional enzymes.

Hence, these are mechanisms to passively lose 5-mC following DNA

replication or to actively remove 5-mC, both potentially returning to

unmethylated cytosine.

Histone posttranslational modifications (hPTMs) are rich sources of

diverse signaling to, and marking of, the chromatin template, including

at least 60 different covalent chemical modifications on the histone

N- and C-terminal tails and within the globular domains. The hPTMs

are added (written) and removed (erased) by enzymes and also serve as

sequence- and PTM-specific binding surfaces for effector proteins and

complexes (readers) to carry out a wide range of downstream actions

3792 PART 20 Frontiers

transcribed genes for future rounds of transcription, whereas histone

SUMOylation plays a role in transcriptional repression. Polyubiquitination serves to tag proteins for degradation by the proteasome,

and dysfunction in this system may play a role in the pathogenesis

of neurodegenerative diseases, including Alzheimer’s, Parkinson’s,

and Huntington’s. ADP-ribosylation involves a class of enzymes, the

poly-ADP-ribose polymerases (PARPs), which transfer ADP-ribose

units from NAD+ to a variety of nuclear proteins. This PARylation

alters the chromatin environment through the recruitment and modification of chromatin-associated proteins. In general, future studies

of the profuse types and functions of hPTMs will enhance our understanding of these chromatin-based mechanisms and processes and will

illuminate new opportunities and targets for therapies.

In contrast, there is extensive understanding of histone lysine

acetyltransferases (KATs) and methyltransferases (KMTs). KATs, previously known as HATs, were among the first identified histone modification enzymes. They attach acetyl groups on the lysine residues of

histone tails and other proteins, resulting in both a novel side chain

(acetyl-lysine) and an increase in negative charge (from positive

charged lysine to neutral acetyl-lysine). This alteration results in

loosening of chromatin structure to become more permissive to the

binding of transcription factors, and acetylation also creates a novel

binding surface for the association of reader proteins. Acetylation

on core histones, such as lysine 9 on histone H3 (H3K9ac) or lysine

27 (H3K27ac), is typically associated with transcriptional activation.

Acetylation is very dynamic and can be rapidly removed by histone

deacetylases (HDACs), of which there are multiple classes, including

HDACs and sirtuins (NAD-dependent deacetylases), acting to return

the lysine to unmodified ground state.

Methylation of histone tails by KMTs provides more nuanced

regulation, in that particular methylated lysines are associated with

transcriptional activation (e.g., H3K4me3, H3K36me3, H3K79me3),

transcriptional repression (e.g., H3K27me3), or DNA repeat and centromeric silencing (e.g., H3K9me3). The output is strictly determined

by effector protein binding, as methylation of lysine does not alter side

chain electrostatic charge. Lysine methylation is also a more stable

chemical modification than is acetylation and turns over more slowly.

Lysine demethylases have been identified for several of the specific

methylated sites (H3K4, H3K9, H3K36, H3K27, H3K79).

In addition to their impacts upon local chromatin structure through

electrostatic alterations and through recruitment of reader effector

proteins, some histone modifications can influence other epigenetic

processes. For example, H3K36me3 is involved in a variety of transcriptional processes including elongation and splicing. However,

through its recruitment and interaction with other methyltransferases,

such as DNMT3B and METTL14, H3K36me3 impacts both DNA and

RNA methylation, respectively.

Frequently coordinating with histone modification enzymes are

nucleosome remodeling enzymes, which use the energy derived from

the hydrolysis of ATP to reposition and remove nucleosomes along

the DNA template and to exchange core histones and variant histones

(including variants that are located at the transcriptional initiation

sites [H2AZ] and over the transcribed genes [H3.3]). The nucleosome

remodeling complexes can activate or repress transcription. The SWI/

SNF family creates nucleosome-free regions for transcriptional activation, the ISWI family evenly spaces nucleosomes to repress transcription, and the INO80 family exchanges H2A with H2AZ at transcription

start sites to poise transcriptional activation. Other remodeling complexes play key roles in the DNA damage response and apoptosis,

among additional genomic processes.

As alluded to above, RNA can also be methylated, and “RNA epigenetics” is now an emerging area of gene regulation beyond the direct

methylation of DNA and hPTMs. Methylation of RNA, such as messenger RNAs (mRNAs), has been known to exist for over half a century.

However, in the last decade, the discovery of enzymes that perform

reversible methylation of RNAs led to an explosion of this new field,

called epitranscriptomics. Indeed, RNA methylation leads to mRNA

degradation or facilitates translation. However, mRNA methylation

itself occurs co-transcriptionally. Notably, the writer methyltransferase

enzymes (METTL3, METTL14) and the demethylases (ALKBH5,

FTO) have important roles in a variety of disease pathologies.

Because multiple enzymes redundantly and synergistically write,

erase, and recognize these modifications on DNA, RNA, and histones,

there is great complexity and the potential for fine-tuning of gene

regulation. While extensive knowledge gaps remain to fully explicate

these mechanisms of gene regulation, epigenetics has become a fully

established discipline within biomedical research. In the coming years,

it is likely that the basic understanding of these processes will be further harnessed for further betterment of human health.

■ EPIGENETICS IN DEVELOPMENT AND

DIFFERENTIATION

Epigenetic processes are critical to organismal development and to

cellular differentiation and reprogramming of cell fate (Fig. 483-1).

Transcription factors establish the epigenomic landscape that enables

and stabilizes cell-type-specific gene expression while simultaneously

ensuring stable repression of alternative cell fates. This results in chromatin profiles that display remarkable cell-type specificity in differentiated cells, particularly at the key regulatory nodes of gene enhancers,

which are gene-distal DNA elements that control transcription. In fact,

epigenome profiling of the chromatin landscape in tumors of unknown

cell origin can provide a better index of the origin tissue than does

DNA sequencing of gene mutations within the tumor.

The cell-type-specific epigenetic program is first derived from the

template of embryonic stem cells, where numerous genes required

for differentiation exist in a “bivalent” state, marked by both the

activating histone modification, H3K4me3, and the repressive modification, H3K27me3. Due to this unstable epigenetic state, the genes

are “poised” for activation or for repression, depending on their

subsequent cell fate. Critical genes directing toward a specific cell fate

will be turned on, with maintained H3K4me3 and erased H3K27me3,

whereas genes leading toward alternative fates will be repressed, with

maintained H3K27me3 and removed H3K4me3. Once differentiated,

an epigenetic barrier will prevent the cells from returning to the stem

cell state. For example, constitutive heterochromatin in the form of

H3K9me3 can serve as a barrier to cellular reprogramming when

attempting to create induced pluripotent stem cells, and inhibiting

the enzymes that catalyze H3K9me3, such as SUV39H1, can enhance

reprogramming efficiency.

DNA methylation contributes to the specification of cell fate and

to other developmental pathways. DNA methylation alterations are

involved in critical processes ranging from sex chromosome dosage

compensation to coordinating expression of imprinted genes. Disruption of this latter process can lead to imprinting disorders including

Prader-Willi syndrome, Angelman syndrome, and Beckwith-Wiedemann

syndrome.

Beyond embryonic development, epigenetics can provide the necessary coordination and balance between adult stem cell self-renewal

compared to cell differentiation. This epigenetic control is critical, as

impaired self-renewal can lead to stem cell exhaustion and premature

aging, while excessive self-renewal may promote cancer. Key epigenetic

regulators tend to play conserved roles across diverse tissue types. For

instance, BMI1, a component of the polycomb repressive complex 1

(PRC1), is required for stem cell proliferation and self-renewal, and

its ablation leads to stem cell depletion in hematopoietic, epidermal,

muscle, intestinal, and mammary stem cells. Similarly, the DNA methyltransferase DNMT1 is required for stem cell self-renewal in hematopoietic, epidermal, and mammary stem cells. HDACs 1 and 2 possess

some overlapping functions and are required for normal epidermal

differentiation. Likewise, a loss of these HDAC enzymes in hematopoietic stem cells can lead to failure of differentiation and severe anemia.

These factors represent repressive chromatin regulation, leading to the

general concept that restraining specific transcription pathways related

to differentiation are crucial to maintaining undifferentiated selfrenewing stem cell pools.

The epigenetic regulation of the tumor suppressor p16 (CDKN2A)

locus during differentiation provides a prime example of this finely

tuned system. For example, as mentioned above, DNMT1 is necessary

3793The Role of Epigenetics in Disease and Treatment CHAPTER 483

for self-renewal in human epidermal stem cells. Levels of DNMT1 are

high in the basal undifferentiated layer of the epidermis, decreasing

progressively with epidermal stratification, leading to de-repression

of the tumor suppressors p16 and p15, thereby promoting cell cycle

arrest and full differentiation. BMI1 displays a similar phenotype in

both hematopoietic and epidermal stem cells, repressing key genes that

promote differentiation, such as p16 and p19ARF. Consistently, a loss

of BMI1 leads to premature differentiation and defective self-renewal.

In addition to the repression provided by DNMT1 and BMI1, the p16

locus is highly decorated with the repressive H3K27me3 catalyzed by

EZH2 in epidermal stem cells. Then, during epidermal differentiation,

H3K27me3 is removed by the KDM6B (JMJD3) histone demethylase.

Loss of this control over programmed p16 expression occurs in epithelial cancers, such as squamous cell carcinoma (SCC), where EZH2 is

overexpressed and KDM6B expression is lost. Breast cancer is another

example where progesterone can increase levels of EZH2 to promote

mammary epithelial cell proliferation, and excessive EZH2 expression

can occur in cancer. This exemplifies how epigenetics can integrate

environmental signals and have a profound influence on the fine

balance between stem cell maintenance and overt carcinogenesis. In

general, a recurrent theme in cancer is loss of key chromatin regulation

that promotes cell differentiation, combined with gain of activities that

promote stemness.

Chromatin-modifying enzymes also play a major role in influencing cell-type specificity. High levels of EZH2 that modify H3K27me3

promote adipogenesis while simultaneously inhibiting osteogenesis. In

contrast, the H3K27me3 demethylases, KDM6A (UTX) and KDM6B,

derepress those same genes, driving stem cells toward osteogenesis.

Through interactions with tissue-specific master regulators, epigenetic

modifiers also shape cell-type specificity. In the epidermis, p63, the p53

family member that is a master regulator of the epidermal compartment, interacts with several chromatin regulators including HDAC1

and HDAC2, SATB1, MLL4 (KMT2D), and BRG1 to orchestrate

epidermal differentiation. Similarly, the gene-activating H3K4 histone

methyltransferases, MLL3 (KMT2C) and MLL4, are required for

adipogenesis by forming a complex with the transcriptional activator

ASC2 and the transcription factor PPARγ to induce adipogenic genes.

Overall, loss of epigenetic regulation can reduce cell differentiation and

increase stem cell specification to drive diseases encompassing development, cancer, and, broadly, diseases associated with aging.

■ EPIGENETICS OF METABOLISM

One of the fascinating aspects of epigenetics is that it represents a

mechanism for direct connection between the environment and gene

expression. Numerous studies in the field of metabolism have identified a complex interplay between diet, metabolism, and the epigenome

(Fig. 483-1). Seminal findings in Drosophila and mice have shown that

changes in diet, particularly the paternal diet, and other environmental

factors, can influence the metabolism of offspring, ultimately promoting obesity in later generations. Epidemiologic studies in humans have

supported these results, as the nutritional status of grandparents has

been correlated with phenotypic effects in grandchildren. In fact, diet

can directly affect the levels and activity of chromatin modifiers.

For instance, high-fat diets reduce histone acetylation through their

ability to inhibit the enzymes ACLY and ACSS2, which produce acetylCoA. Levels of acetyl-CoA, in comparison to all measured metabolites,

are indeed the best predictor of histone acetylation levels. Consistent

with this, increased acetyl-CoA correlates with rising levels of total

histone acetylation, including at the promoters of growth-associated

genes. This increase in nuclear acetylation is associated with cell cycle

progression and proliferation, and it can have clinically relevant downstream effects. For example, high levels of acetyl-CoA can delay stem

cell differentiation and suppress autophagy. The oncogenes MYC and

AKT can both hijack metabolic networks to enhance nutrient uptake

by cancer cells, thus promoting acetyl-CoA production and resulting in

both the initiation and progression of tumorigenesis. Recent evidence

suggests that dietary intake of alcohol can directly contribute to acetate

levels and therefore histone acetylation in the brain, with effects on the

transcription of genes involved in learning and memory.

Contrary to convention that metabolic enzymes are strictly mitochondrial or cytosolic, certain metabolic enzymes can be present

in the nucleus and can thereby directly regulate histone acetylation

enzymes. This is the case for several enzymes that generate acetylCoA, including ACLY, PDH, and ACSS2, which generate acetyl-CoA

from citrate, pyruvate, and acetate, respectively. Further, ACSS2 can be

chromatin-bound to regulate gene expression, leading to physiologic

responses such as autophagy in the liver and mammalian hippocampal

function in learning. This direct metabolic-epigenetic enzyme crosstalk illuminates a crucial local role of the acetyl-CoA metabolite to

effect rapid gene transcription and represents a fertile intersection for

future therapeutics.

Methylation is also altered by metabolism. S-adenosylmethionine

(SAM) is the key metabolic co-factor for histone and DNA methylation.

Dietary factors are estimated to explain 30% of the variation in human

serum methionine concentration and hence can alter SAM levels and

histone methylation. For example, dietary methionine availability and

intracellular production of SAM affect the levels of histone H3K4me3

associated with transcriptional activation. Furthermore, these fluctuations can have critical physiologic consequences: DNA methylation

levels in rectal mucosa and colonic polyps are increased by higher

levels of dietary folate, and a diet low in methyl donors reduces the formation of gastrointestinal cancers in mice predisposed to these tumors.

Methionine metabolism and the availability of SAM regulates stem cell

differentiation and contributes to carcinogenesis. For instance, cancers

with mutations in metabolic regulatory genes such as IDH1/2, FH, and

SDH lead to the accumulation of by-products (2-hydroxyglutarate,

fumarate, and succinate, respectively), which all inhibit α-ketoglutarate

(α-KG)–dependent histone demethylases and thus promote hypermethylation and lead to impaired cellular differentiation. Notably,

some of the α-KG–dependent demethylases, which are highly mutated

in numerous cancers (i.e., KDM5A, KDM6A), also serve as cellular

oxygen sensors, thus linking environmental oxygen levels to epigenetic

control of methylation levels. In contrast to hypermethylated states,

loss of the MTAP gene, which is part of the 9p21 locus containing p16

and one of the most frequent events in human cancer, disrupts normal

methionine metabolism. This both lowers methylation levels, and,

interestingly, also sensitizes cancer cells to inhibitors of the PRMT5

methyltransferase, therefore opening a new therapeutic opportunity.

These observations illustrate how connections between epigenetics

and metabolism can generate unanticipated advances in medicine.

Furthermore, these data highlight the tight interconnections between

environmental inputs, metabolism, and epigenetics.

■ CANCER EPIGENETICS

Cancer is now understood to be a mixed genetic and epigenetic disease,

as epigenetic dysregulation is pervasive in human cancers (Fig. 483-1).

Beyond simple activation of oncogenes or reduced expression of tumor

suppressors, epigenetic mechanisms can contribute to chemotherapy

resistance and to failure of antitumor immunity. Accordingly, the

development of drugs targeting epigenetic pathways is one of the most

active areas of clinical and pharmaceutical development, with several

compounds already approved for human use and shown to be effective

in a variety of cancers. Epigenetic perturbations in cancer largely affect

chromatin-regulating enzymes, which represent robust targets for

development of novel small-molecule inhibitors, especially as compared with canonical oncogenic transcription factors (e.g., MYC) and

tumor suppressors (e.g., p53).

Epigenetics can contribute to carcinogenesis in a variety of ways.

First, on a global scale, chromatin organization is the single most influential factor in determining local mutation rate across the genome.

Analysis of abundant tumor sequencing data has demonstrated that

heterochromatic regions of the genome contain a higher frequency of

mutations compared with more open euchromatic regions. This difference is due to the improved accessibility of the DNA repair machinery

to less compact, more open regions of chromatin.

The first discovery of an epigenetic mutation was found in 1998

when the chromatin remodeler SMARCB1 was shown to drive the formation of malignant rhabdoid tumors. Extensive sequencing of human

3794 PART 20 Frontiers

tumors from the majority of cancer types has been performed by The

Cancer Genome Atlas (TCGA) consortium, and remarkably, 25–30%

of identified cancer driver mutations occur in chromatin regulatory

proteins. Similar to SMARCB1, numerous other chromatin modifiers (e.g., methyltransferases MLL3 and MLL4, and acetyltransferases

EP300 and CBP) and nucleosome remodeling enzymes and associated

complex components (e.g., SMARCA4, SMARCA2, ARID1A) are heavily mutated and inactivated in many cancers. The majority of these

mutations are loss-of-function mutations, and indeed, enzymes like

MLL4 and demethylase KDM6A possess tumor-suppressive activity.

In contrast, the H3K27me3 histone methyltransferase EZH2 is an

oncogene, and accordingly, it is overexpressed in many advanced-stage

or metastatic solid tumors such as breast cancer, prostate cancer, and

melanoma. Mechanistically, EZH2 represses the p16 tumor suppressor

and other cell cycle genes required for cell cycle exit via H3K27me3

deposition. Consistent with a broad growth regulatory role, EZH2

inhibitors are therapeutically successful for a number of cancers in

preclinical models and are being actively studied for B-cell lymphoma,

melanoma, and other solid tumors.

Recently, provocative evidence has emerged for a direct tumorigenic

role of histones based on the discovery of causative mutations, such

as histone H3 mutations identified in pediatric high-grade gliomas.

Specifically, the majority of these mutations are in the H3 variant H3.3,

where lysine 27 is replaced by methionine (K27M). Similarly, >90%

of chondroblastomas replace lysine 36 with methionine (K36M) in

histone H3.3. These effects appear to be dominant negative because

(1) in H3.3 these are heterozygous mutations, and (2) the mutations

also occur in the canonical H3, which exists in ~30 orthologous genes

in the human genome. Thus, a minority of H3/H3.3 mutant protein

leads to global defects in the associated histone modifications (K27 or

K36 methylation), possibly via irreversible inhibition of the cognate

enzymes by the mutant histones. These “oncohistone” mutations promote resistance to apoptosis and failure of normal differentiation in a

number of pediatric and adult cancers.

Beyond mutations, genetic translocations involving chromatin modifiers also implicate chromatin pathways as direct drivers in cancer.

MLL1 (KMT2A), the H3K4 histone methyltransferase, is a frequent

translocation partner occurring in adult and pediatric acute myeloid

leukemia (AML) and in ~80% of infant acute lymphoid leukemia

(ALL) cases. MLL1 can fuse with >70 translocation partners, and these

mutant proteins prevent normal hematopoietic differentiation. Consistent with a causative role of MLL1 in these gene fusions, drugs inhibiting the catalytic activity of MLL1 are effective in preclinical models of

AML and are currently being evaluated in human clinical trials.

Given the abundance of epigenetic abnormalities in cancer combined with the inherent reversibility of epigenetic changes, extensive

efforts are underway to develop epigenetic drugs. The first epigenetic

therapeutic involved the use of DNA methylation inhibitors (DNMTi)

to reactivate tumor-suppressor genes. Interestingly, the mechanism

of traditional chemotherapeutics, such as azacitidine and decitabine, is

to inhibit DNMT1, thereby promoting global hypomethylation; these

are currently in clinical use for myelodysplastic syndrome (MDS) and

AML. In a second broad mechanism, loss of acetylation occurs in

many cancers, and thus, HDAC inhibitors (HDACi) are under intensive development. HDACi are effective and approved for treatment in

cutaneous T-cell lymphoma and multiple myeloma. Bromodomain

(BRD)-containing proteins bind to lysine acetylated target proteins,

including histones, and rationally designed BET inhibitors (BETi)

block their binding. BETi reduce the amplified expression of oncogenes

such as MYC in hematologic cancers. Current studies are now focused

on optimizing combinatorial epigenetic therapies with conventional

chemotherapies and immunotherapies, particularly given the ability

of epigenetic therapeutics to promote reexpression of tumor antigens

and interferon (IFN)-mediated antitumor immunity. Indeed, the

development of a new generation of more specific epigenome-targeted

inhibitors, combined with our increased knowledge of the underlying

epigenetic mechanisms contributing to tumorigenesis, has enabled a

precision medicine–based approach to harnessing the potential of these

drugs. This may be particularly valuable in the context of improving

patient responses to a variety of therapies beyond chemotherapies and

immunotherapies, such as radiation and hormone therapies.

There are several hundred chromatin enzymes and binding proteins

in the human genome, and the current focus is to identify more specific

inhibitors. Indeed, targeted inhibitors of numerous mutated chromatin regulators have been developed, with >30 compounds currently

in various stages of development and preclinical trials. Some notable

examples showing early clinical success include EZH2 inhibitors for

lymphomas, sarcomas, and melanoma, IDH inhibitors for AML and

gliomas carrying mutant IDH1 or IDH2 genes, LSD1 inhibitors for

AML and small-cell lung cancer, and DOT1L and MLL1 inhibitors for

leukemias with activated MLL1. Given the broad potential effects of

epigenetic regulators, it is perhaps not surprising that there have been

some dose-limiting toxicities, particularly among those that are less

target-specific. Collectively, the emerging picture is that the most effective and robust use of epigenetic drugs in cancer will be fine-tuning

and potentiating the effects of other therapies that are either incompletely effective or marked by widespread resistance.

■ EPIGENETICS OF AGING

Like many diseases of aging, human aging itself results from the

complex interplay between genes and the environment. Evidence

that the epigenome may be the key link between these processes

derives from observations that numerous environmental stimuli and

stressors—ranging from diet and exercise to hormones and circadian

rhythms—contribute to both aging and epigenetic alterations (Fig. 483-1).

Thus, a lifetime of exposures progressively disrupts the chromatin

landscape. These age-dependent changes in chromatin organization

increase the susceptibility of the genome to mutations and also reduce

transcriptional fidelity. Further, provocative findings in model systems

demonstrate that stress-induced epigenetic changes can be transmitted

over several generations and can even affect the life span of later generations. Among these global epigenetic alterations, there is dysregulation of histone modifications and a general loss of histone proteins

with aging across taxa. Amazingly, experimental increases in histone

levels, particularly histones H3 and H4, but not H2A or H2B, can

reverse these age-related changes in mammalian cells and in the yeast

Saccharomyces cerevisiae model.

Thus, the sum of current evidence suggests a model of aging via a

general increase in activating epigenetic modifications along with a loss

of repressive modifications. Together these changes create a state of

transcriptional instability and “noise” that inhibits accurate transcription. Cells from patients with Hutchinson-Gilford progeria syndrome

(HGPS), the most severe form of human premature aging, display

reduced levels of both H3K9me3 and H3K27me3 repressive chromatin.

In another premature aging disease, Werner syndrome, DNA damage

induces global loss of H3K9me3 and H3K27me3 due to the inherent

absence of the Werner syndrome ATP-dependent DNA helicase, which

is critical for DNA repair. Such heterochromatin loss is not limited to

premature aging conditions, as aged cells derived from healthy older

humans display age-dependent loss of H3K9me3 leading to aberrant

expression of normally repressed transposable elements. Activation

of these mobile elements correlates with neurodegenerative disorders

and may also promote other aging-related phenotypes such as cancer.

Human fibroblasts undergoing cellular senescence (exit from cell cycle

due to replicative or other stress) undergo destabilization of compact heterochromatin adjacent to the nuclear periphery, in so-called

lamin-associated domains (LADs). At LADs, in addition to a reduction

of repressive histone modifications as discussed above, there are broad

new regions of the euchromatic histone modification H3K4me3. This

general loss of heterochromatin can promote the activation of cytosolic

DNA and RNA sensing pathways that promote innate immune signaling and “inflammaging.”

In addition to age-associated alterations of histone modifications,

direct manipulation of chromatin-modifying enzymes that control

these marks affects the balance between heterochromatic and euchromatic regions, and it alters the life span of model organisms. Inhibiting

the H3K27me3 histone demethylase KDM6A results in increased

repressive H3K27me3 and extended life span in Caenorhabditis elegans.

3795The Role of Epigenetics in Disease and Treatment CHAPTER 483

Consistent with this, genetic reduction of enzymes (ash-2, set-2, wdr-5)

that add the activating H3K4me3 histone modification also extends life

span in C. elegans. The consequences of these genetic manipulations

nicely correspond to the observed changes in histone modifications as

described above. Beyond histone-modifying enzymes, dysregulation of

the levels or function of chromatin remodelers can also affect life span

in model organisms. This dysregulation occurs in humans as well, as

in the nucleosome remodeling deacetylase complex (NuRD), which is

reduced in HGPS fibroblasts and in aged healthy donors.

In addition to age-related changes in histone methylation, histone

acetylation also contributes to aging phenotypes. Dysregulation of histone acetyltransferases (HATs) and HDACs is associated with reduced

longevity across model organisms. Further, sirtuin deacetylases (class III

NAD+-dependent HDACs) promote health span and life span across

species as key mediators of pro-longevity effects of caloric restriction.

Indeed, loss of Sirt6 results in premature aging in mice, while caloric

restriction–induced increases of Sirt1 and Sirt6 expression can delay

aging. As discussed previously, metabolism and acetylation are intricately linked, and the sirtuins, via NAD+ levels, and other HDACs

may play key roles connecting the environment, gene expression, and

physiologic output. For instance, exercise in humans reduces activity

of HDACs 4 and 5, leading to increased H3K36ac in skeletal muscle,

which likely promotes beneficial gene expression.

Epigenetic alterations with aging are not limited to histone modifications and extend to DNA methylation. Consistent with the histone

patterns, DNA methylation data support the model described above—

that is, general decompaction of the epigenome with aging. Specifically,

levels of 5-methylcytosine (5-mC) are reduced in senescent human

cells, and global DNA hypomethylation occurs across the human

genome with aging. Concurrent with this overall hypomethylated state,

there are local regions of hypermethylation focused near CpGs at gene

promoters, particularly at genes that maintain cellular differentiation

and cell identity. This epigenetic disruption during aging thus leads

to profound changes in transcription. For example, in hematopoietic

stem cells, DNA hypermethylation blocks proper binding of transcription factors, resulting in dysregulation of normal gene expression with

aging. Importantly, these patterns are not merely stochastic alterations

in response to environmental stressors throughout aging. Indeed, the

methylation status of a defined number of CpG sites is a highly accurate predictor of chronologic age in human tissues. This work reveals

that DNA methylation status with aging outperforms previous standard biomarkers of aging, such as p16 expression levels and telomere

length, and will be highly valuable in the near future to gauge effects of

treatment aiming to ameliorate diseases of aging.

■ EPIGENETICS OF THE BRAIN AND BEHAVIOR

Brain disorders are among the greatest clinical challenges to understand and to treat. Most neurologic and psychiatric disorders result

from complex dysregulation of numerous genes and pathways. In

this interplay between underlying genetic predisposition and external

environmental factors, aberrant epigenetic regulation is increasingly

recognized as a potentially key modulator (Fig. 483-1).

More directly, however, several progressive neurodevelopmental

disorders are caused by germline mutations in chromatin regulators.

Mutations in methyl CpG binding protein 2 (MECP2), a protein

important for binding to methylated DNA and contributing to gene

repression, are the major cause of Rett syndrome. MeCP2 loss leads

to overactive gene transcription in neurons and impaired presynaptic

excitatory functions. Similarly, Kabuki syndrome, another progressive

neurodevelopmental disorder, is caused by germline mutations in

either the H3K4me1 histone methyltransferase, MLL4 (KMT2D), or

the H3K27me3 demethylase, UTX (KDM6A). This disorder may derive

from dysregulation of transcriptional enhancers, a major class of gene

regulatory elements, as both MLL4 and UTX play a key role in activation of enhancers. Finally, the acetyltransferase CBP (CREBBP) also is

important for gene enhancer function and, when mutated, can lead to

Rubinstein-Taybi syndrome, a cause of intellectual disability.

Beyond germline mutations, altered methylation dynamics can

drive disorders of neural development and of neurodegeneration.

Fragile X syndrome, characterized by learning disabilities and cognitive impairment, is caused by mutations in the FMR1 or FMR2 gene or

by hypermethylation of the transcriptional promoters regulating FMR1

or FMR2. Similarly, Prader-Willi syndrome and Angelman syndrome,

neurodevelopmental conditions caused by abnormal imprinting of the

paternal or maternal chromosomal region (15q11-13), respectively,

are frequently caused by aberrant DNA methylation. Further, DNA

hypomethylation is implicated in some neurodegenerative conditions. For instance, in Parkinson’s disease, several genes involved in

pathogenesis are hypomethylated due to DNMT1 depletion, including

the α-synuclein gene (SCNA). In Alzheimer’s disease (AD), DNA

hypomethylation occurs at promoters of key pathogenic genes such as

amyloid precursor protein (APP). Indeed, APP promoter methylation

is responsive to environmental factors, including aging, a major risk

factor for AD. Likewise, presenilin-1 (PSEN1) is implicated in AD

and displays altered DNA methylation in response to variations in

metabolic stimuli. Recent evidence from human AD brains demonstrated significant enrichment of H3K9 and H3K27 acetylation and

provided evidence that this dysregulation of the epigenome promotes

gene transcription pathways involved in AD pathogenesis. Studies of

Huntington’s disease (HD) have demonstrated DNA hypomethylation

and decreased histone acetylation, in part due to altered function of

the acetyl transferase CBP, leading to transcriptional dysregulation.

Together, these observations underscore altered epigenetic regulation

as a crucial feature of neurodegeneration.

Additional gene regulatory proteins in the nervous system interact

with and are regulated by chromatin modifiers. REST (repressor element 1–silencing transcription factor) is important in neuronal homeostasis through its ability to recruit chromatin regulatory enzymes, such

as histone deacetylases and histone methyltransferases, and via its

control over gene expression. REST levels increase with aging and

serve a protective function in neurons against age-associated stressors

and loss of cognitive function associated with AD. Similar to REST,

brain-derived neurotrophic factor (BDNF), another important mediator of neural development and homeostasis, is implicated in a variety

of neurologic and psychiatric disorders including HD, depression,

schizophrenia, bipolar disorder, and autism. Knockdown of BDNF in

the dentate gyrus leads to depression-like behavior in mouse models,

and BDNF mediates effects of antidepressant therapies. Chromatin

pathways, including DNA methylation/MeCP2 and H3K27me3, play a

key role in BDNF regulation as observed in brains from patients with

schizophrenia.

Finally, addiction medicine is another frontier where epigenetics

holds great promise to reveal connections between environmental

exposure and phenotypes. Although still in its early stages in terms of

mechanistic understanding, emerging evidence demonstrates disruption of epigenetic homeostasis as a consequence of addictive substances

ranging from alcohol to cocaine. For example, the acetylation of regulatory elements in the FOSB gene by the histone acetyltransferase CBP is

associated with behavioral effects of cocaine. Opioid exposure appears

to promote a generally more open and permissive state of chromatin

marked by increases in histone acetylation and reductions in histone

methylation, which may allow for a more hyperresponsive state and

reinforce reward-seeking behaviors. Ethanol also induces histone acetylation and a decompacted chromatin structure with direct effects on

learning and memory function.

■ EPIGENETIC INFLUENCES ON INFECTION,

IMMUNITY, AND INFLAMMATION

Alterations in gene expression patterns are important determinants of

immune-mediated disease, and in turn, epigenetics regulates infection,

immunity, and inflammation (Fig. 483-1). Treatment with immunestimulating agents such as lipopolysaccharide (LPS) and tumor necrosis factor α activate expression of numerous inflammatory genes within

hours, with precise gene pathways and activation kinetics determined

by the cellular epigenetic state. HATs and HDACs are critical components of this response, coordinating with proinflammatory transcription factors such as AP-1 and NF-κB, to activate (HATs) and to repress

(HDACs). For example, corticosteroids recruit HDAC2 to promoters