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Beyond DNA: The Invisible Forces Shaping Life
In 2000, world leaders proclaimed the human genome sequence humanity's greatest achievement-the language of creation itself. But these declarations were premature. The Dutch Hunger Winter provides a startling counterexample: children whose mothers experienced famine during pregnancy developed different health outcomes despite identical genetics. Similarly, identical twins with the same DNA often develop different diseases and personalities. Something beyond DNA must explain these phenomena. Enter epigenetics-the revolutionary science explaining how genetically identical individuals become non-identical, and how environmental factors create lasting biological consequences. This field has transformed our understanding of development, disease, and inheritance, becoming one of biology's most exciting frontiers. Nessa Carey's groundbreaking book has been hailed by researchers as the definitive introduction to this complex subject, praised for making intricate molecular mechanisms accessible while maintaining scientific accuracy. As Francis Collins, former director of the Human Genome Project noted, "Understanding epigenetics is essential for understanding the true nature of life's blueprint."
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The Elegant Experiments That Revealed Our Epigenetic Nature
How can cells with identical DNA become so dramatically different? This fundamental question drove John Gurdon's revolutionary experiments with African clawed toads in the 1960s. Despite his biology teacher once declaring his scientific ambitions "quite ridiculous," Gurdon designed an elegant experiment to test whether specialized cells permanently lose genes they don't need.
Using somatic cell nuclear transfer (SCNT), Gurdon extracted nuclei from adult toad intestinal cells and placed them into unfertilized eggs whose own nuclei had been removed. Remarkably, some of these eggs developed into healthy tadpoles, proving that differentiated cells retain all genetic information-they simply express different genes. This groundbreaking discovery showed that while epigenetic modifications can control gene expression for decades, the underlying DNA sequence remains unchanged.
Conrad Waddington's metaphorical "epigenetic landscape" from 1957 provides a powerful visual model for understanding cellular development. Imagine a ball (representing a cell) rolling down a hillside with various grooves and valleys. As the ball descends, it becomes increasingly difficult to move between pathways-just as specialized cells rarely transform into other types. Gurdon's experiments demonstrated that with sufficient intervention, a cell from the bottom of a developmental pathway could be returned to the top and regain its developmental potential.
This concept explains why cloning remains inefficient and why cloned animals often suffer health problems. When Dolly the sheep was created in 1996, scientists needed nearly 300 attempts to produce one healthy animal. The challenge wasn't copying the DNA-it was resetting the complex epigenetic barriers that maintain cellular identity. While nature accomplishes this reprogramming effortlessly during normal reproduction, our artificial methods remain crude by comparison.
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Climbing Back Up the Epigenetic Mountain
Fast-forward thirty years from Gurdon's work to a laboratory in Japan where another scientist, Shinya Yamanaka, discovered a completely new approach to cellular reprogramming. Despite media portrayals suggesting mammalian cloning had become routine, the process remained technically challenging, time-consuming, and costly. Scientists dreamed of a simpler approach: taking accessible cells from an adult mammal and treating them with specific factors to make them behave like newly fertilized eggs.
At the top of Waddington's landscape sits the zygote-a totipotent cell capable of forming every cell in the body, including the placenta. Scientists typically work with slightly later embryonic stem (ES) cells derived from the blastocyst. These pluripotent cells can form virtually any body cell except the placenta and can divide limitlessly while maintaining their identity under laboratory conditions.
While most scientists assumed recreating the complex conditions of ES cells would be nearly impossible, Yamanaka and his postdoc Kazutoshi Takahashi decided to test this assumption. They engineered cells with a neomycin resistance gene that would activate only if cells became pluripotent, allowing them to survive when exposed to an otherwise lethal antibiotic. Using specially designed vectors as "Trojan horses," they introduced 24 candidate genes into fibroblasts. Through systematic elimination, they discovered that just four genes-Oct4, Sox2, Klf4, and c-Myc-could transform differentiated cells into ES-like cells capable of developing into all three major tissue types. Yamanaka called these "induced pluripotent stem cells" (iPS cells).
The scientific community initially greeted this breakthrough with skepticism until Rudolf Jaenisch, a renowned genetic engineering expert, confirmed the results at a 2007 conference in Colorado, triggering an explosion of research in the field.
The economic implications are enormous. For diseases like type 1 diabetes, iPS cells could revolutionize treatment, potentially saving billions in healthcare costs. The technology also shows promise for blood clotting disorders, Parkinson's disease, osteoarthritis, macular degeneration, and tissues destroyed by cancer. The U.S. Department of Defense is funding iPS cell research for combat medicine, particularly focusing on red blood cells which, lacking nuclei, are relatively safe for clinical use.
Despite these remarkable advances, nature still outperforms our technology. When sperm and egg fuse naturally, reprogramming happens with extraordinary efficiency within 36 hours, while artificial reprogramming remains slow and inefficient. The difference lies in epigenetics: the egg cytoplasm acts as a molecular eraser, rapidly removing differentiation-specific epigenetic signatures that our artificial methods struggle to replicate.
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The Genetic Blueprint and Its Epigenetic Editors
To understand epigenetics, we must first grasp genetics. DNA provides the blueprint for life, but proteins do the actual work in our cells. The DNA code consists of just four letters (bases): adenine (A), cytosine (C), guanine (G), and thymine (T), with cytosine being most crucial for epigenetics. DNA resembles a twisted zipper with two strands held together by base pairs following strict pairing rules: A with T, and G with C.
This base-pairing principle enables faithful DNA replication before cell division. When cells divide, the DNA strands separate, and the replication complex builds new complementary strands using these pairing rules. Though occasional errors occur, repair proteins quickly identify and fix mismatches. This meticulous copying process is essential-just as one wrong letter can change Shakespeare's "wherefore art thou" to "wherefore fart thou," a single DNA mutation can have devastating effects.
Our six billion DNA base-pairs function like a modular system-comparable to Lego bricks. Just as Lego's limited range of pieces can create countless models, the twenty standard amino acids in our cells combine to form thousands of different proteins. DNA is read in blocks of three base-pairs (codons), with messenger RNA (mRNA) serving as an intermediary, similar to creating PDFs from original digital files.
Most human genes contain both exons (expressed sequences that code for amino acids) and introns (unexpressed sequences). When DNA is first copied to mRNA, it contains both elements, but a complex splicing process removes the introns and joins the exons. Crucially, this mechanism allows cells to selectively include or exclude certain exons, enabling a relatively small number of genes to produce a much larger variety of proteins. This explains how just 20,000 genes can generate our complex proteome.
Recent research has shown that genes on different chromosomes can physically loop out and interact in three-dimensional space, coordinating the expression of proteins needed for specific functions like hemoglobin production.
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The Molecular Machinery of Epigenetics
The paradox of cellular specialization lies in how different cells maintain distinct gene expression patterns despite containing identical DNA blueprints. Like actors working from the same Shakespeare script but with different director's notes, cells carry epigenetic modifications that control which genes are expressed without altering the underlying DNA sequence.
DNA methylation was the first identified epigenetic modification-the addition of a methyl group to cytosine bases in DNA. This tiny chemical addition, comparable to sticking a grape on a tennis ball, increases the base-pair weight by just 2.5%. Methylation occurs specifically on cytosine bases that are followed by guanine (CpG sites) and is performed by enzymes called DNA methyltransferases (DNMT1, DNMT3A, DNMT3B).
When genes are active, CpG islands in their promoters have low methylation levels; when genes are switched off, these islands become highly methylated. The protein MeCP2 acts as a "reader" of this code, binding to methylated DNA and recruiting other proteins that help repress gene expression.
The critical role of epigenetic readers became dramatically clear through studies of Rett syndrome, a severe neurological disorder resembling autism. In 1999, Huda Zoghbi's team discovered that Rett syndrome is caused by mutations in the MeCP2 gene. Adrian Bird's groundbreaking 2007 Science paper demonstrated that Rett syndrome could be reversed in adult mice. By engineering mice with an inactivated Mecp2 gene plus a silent normal copy that could be switched on later, Bird showed that previously immobile, severely affected mice suddenly resumed normal exploratory behavior when the gene was activated. This extraordinary result challenged the assumption that complex neurological conditions are irreversible.
DNA isn't a naked molecule but intimately associated with proteins called histones. Four histone proteins (H2A, H2B, H3, H4) form an octamer structure with DNA coiled around it, creating nucleosomes. While initially viewed as mere packaging proteins, histones are now understood to be critical for gene regulation through chemical modifications to their protruding "tails."
David Allis at Rockefeller University demonstrated in 1996 that histone acetylation increases gene expression. Since then, over 50 different histone modifications have been identified, forming a complex "histone code" that can either activate or repress genes. Unlike DNA methylation, which is relatively permanent, histone modifications are plastic and responsive to external stimuli like hormones or drugs-representing how environment interacts with our genes.
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Why Identical Twins Develop Differently
Identical twins have fascinated cultures for millennia, appearing throughout literature from Plautus to Harry Potter. But even more intriguing than their similarities are their differences, which have captivated both artists and scientists. Monozygotic twins form when a single zygote's inner cell mass splits into two embryos that are genetically identical. This random event occurs in about 1 in 250 pregnancies.
Twin studies help determine how genetics influences various conditions by calculating concordance rates-how often both twins develop the same condition. While some conditions like achondroplasia show 100% concordance, most diseases don't, revealing the complex interplay between genetics and other factors.
In 2005, Professor Manel Esteller's team discovered that infant identical twins showed minimal differences in DNA methylation and histone acetylation, but older twins, especially those who had lived apart, showed significant epigenetic variations. This suggests genetically identical twins diverge epigenetically as they age and experience different environments. Dr. Jeffrey Craig's 2010 research further demonstrated that even newborn identical twins already show differences in DNA methylation patterns, indicating epigenetic divergence begins in utero.
The agouti mouse model beautifully demonstrates how epigenetics creates phenotypic differences in genetically identical individuals. Despite identical genetics, these mice display dramatically variable coat colors-from completely yellow to normal banded patterns. The explanation? Differences in DNA methylation of a retrotransposon near the agouti gene. Heavily methylated retrotransposons prevent disruption of normal agouti expression (producing banded fur), while unmethylated ones cause continuous agouti expression (yielding yellow fur). DNA methylation essentially functions as a dimmer switch, creating a spectrum of phenotypes from identical genotypes.
The Dutch Hunger Winter of 1944-45 created a unique scientific study population. Researchers discovered that maternal nutrition during pregnancy had lifelong effects on offspring. Babies whose mothers were malnourished late in pregnancy were born small and remained smaller throughout life with lower obesity rates. Surprisingly, those whose mothers suffered malnutrition only during early pregnancy had normal birthweight but higher obesity rates as adults, along with increased risk of schizophrenia. This supports developmental programming theory-early pregnancy epigenetic disruptions become "set" and maintained for decades, affecting gene expression patterns.
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Can Acquired Traits Be Inherited?
The chapter explores potential Lamarckian inheritance mechanisms through epigenetics. Scientists have historically avoided investigating inheritance of acquired characteristics due to overwhelming evidence against it. However, epigenetic modifications can occur at specific genes in response to environmental influences without changing DNA sequence. These modifications affect gene expression and can be transmitted from parent cell to daughter cell, suggesting a potential mechanism for transmitting environmentally-induced changes across generations.
The Dutch Hunger Winter provides compelling evidence for transgenerational inheritance in humans. Researchers discovered that when pregnant women suffered malnutrition during their first trimester, their babies had normal birth weights but higher adult obesity risk. Remarkably, when these babies grew up and had children, their firstborns tended to be heavier than normal. This effect is puzzling since these grandchildren were never exposed to malnutrition.
Studies from isolated Overkalix in northern Sweden provide evidence for male transgenerational inheritance. Examining historical periods of feast and famine in the late 19th and early 20th centuries, researchers found that if food was scarce during a father's slow growth period (years before puberty), his sons showed decreased cardiovascular disease mortality. Conversely, if a father had abundant food during this period, his grandsons faced increased diabetes mortality risk.
Emma Whitelaw's research showed that the yellow fur trait in agouti mice wasn't simply due to the intrauterine environment. When they transferred fertilized eggs from yellow mothers to dark surrogate mothers (and vice versa), the offspring's coat patterns matched their biological mothers, not their surrogates. Complex breeding experiments ruled out cytoplasmic inheritance, strongly suggesting true epigenetic inheritance through DNA methylation patterns.
The alarming rise in obesity raises questions about transgenerational epigenetic effects. Animal studies show paternal diet directly affects offspring health: male rats fed high-fat diets produced normal-weight offspring with diabetes-like abnormalities, particularly in daughters. Similarly, male mice on low-protein diets fathered pups with abnormal metabolic gene regulation and epigenetic modifications in their livers. These studies suggest a father's diet can transmit epigenetic changes to children, independent of environmental factors.
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The Battle Between Maternal and Paternal Genes
This chapter begins by questioning something we rarely think about: why mammalian reproduction requires both male and female parents. While the fusion of haploid gametes creates a diploid zygote, there's more to mammalian reproduction than just combining chromosomes.
Azim Surani's revolutionary experiments in the mid-1980s proved that mammalian reproduction requires more than just combining genetic material-it matters enormously which parent contributes which DNA. Using micropipettes to transfer pronuclei between fertilized mouse eggs, he demonstrated that embryos develop properly only when they contain one male and one female pronucleus. Despite having identical genetic content, embryos with two male or two female pronuclei invariably died during development.
After fertilization, the epigenetic modifications on both pronuclei undergo dramatic changes-methylation is rapidly stripped from the male pronucleus and more slowly from the female one, essentially wiping the epigenetic memory clean. This reprogramming places the zygote at the top of Waddington's epigenetic landscape, allowing it to develop into all cell types.
Despite extensive epigenetic reprogramming, Surani's experiments revealed a paradox-the male and female pronuclei aren't functionally equivalent, suggesting some epigenetic information must be preserved across generations. Surani's lab discovered that mammals "barcode" DNA in eggs and sperm, with DNA methylation serving as flags marking chromosomes as maternal or paternal in origin.
The evolutionary battle between maternal and paternal genomes has reached a Mexican stand-off through epigenetic mechanisms. Experiments with mouse zygotes containing only maternal or paternal DNA demonstrated this conflict. Neither developed normally-maternal-only embryos had underdeveloped placentas while paternal-only embryos showed better placental development but severely retarded embryonic growth.
Imprinted regions of chromosomes behave differently depending on parent-of-origin. On chromosome 11, paternal copies have active genes promoting placental growth, while maternal copies are switched off to limit this growth and protect the mother. On mouse chromosome 7, the Igf2 gene promotes embryonic growth but is only expressed from the paternal copy. Scientists have identified about 100 imprinted genes in mice and roughly 50 in humans.
When imprinting mechanisms fail, serious disorders result. Prader-Willi syndrome causes low birth weight, floppy muscles, and eventual obesity from constant hunger. Angelman syndrome causes severe mental retardation and spontaneous laughter. Both disorders involve the same region of chromosome 15 but manifest differently depending on parental origin.
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The Complex World of X Chromosomes
The fundamental biological differences between men and women extend to their chromosomes. While humans have 23 chromosome pairs, the sex chromosomes differ between genders-females have two X chromosomes (46,XX), while males have one X and one small Y chromosome (46,XY). The Y chromosome carries only 40-50 protein-coding genes, with the SRY gene driving male development through testosterone production. The X chromosome, however, contains about 1300 genes, many involved in brain function and fertility.
Despite females having two X chromosomes and males only one, expression of X-linked genes is remarkably similar between sexes through dosage compensation. Mary Lyon's predictions about this process have proven remarkably accurate: in female cells, only one X chromosome remains active while the other is epigenetically silenced; inactivation occurs early in development; the choice between maternal or paternal X is random in each cell; and once established, this inactivation remains irreversible throughout the woman's life.
X inactivation makes females epigenetically more complex than males. While males have only one X chromosome expression pattern, females are epigenetic mosaics-their bodies contain two distinct cell populations, each expressing genes from only one of their X chromosomes.
The key to X inactivation was found in the X Inactivation Centre, containing the Xist gene that's only expressed from the inactive X chromosome. Surprisingly, Xist doesn't produce protein-it's a non-coding RNA that never leaves the nucleus. Instead, Xist RNA binds to and "paints" the chromosome that produced it, triggering a cascade of epigenetic silencing. As Xist spreads along the chromosome, it blocks transcription enzymes, removes activating histone modifications, replaces them with repressive ones, and methylates gene promoters.
Tortoiseshell cats provide visible evidence of X-inactivation stability. These cats have patches of orange and black fur because the genes for these colors are on the X chromosome. In female cats with different color genes on each X, random inactivation creates a mosaic pattern as melanocyte stem cells produce clonal patches of either orange or black fur.
Our cells are remarkably good at counting X chromosomes. No matter how many X chromosomes exist in a nucleus, cells can count them and inactivate all but one. This explains why abnormal X chromosome numbers produce relatively mild phenotypes compared to autosomal trisomies like Down syndrome.
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The Hidden Language of Non-Coding RNA
We're experiencing a paradigm shift in biology. For decades, DNA and proteins were the stars of molecular biology, with RNA relegated to being merely an intermediate messenger. The discovery that humans have roughly the same number of protein-coding genes as the simple nematode C. elegans challenged our understanding of genomic complexity. What truly scales with organism complexity isn't gene count but the percentage of non-protein-coding DNA-bacteria use 90% of their genome for protein coding, while humans use just 2%.
The term "non-coding" has misled scientists for decades. These genomic regions don't code for proteins, but this doesn't mean they don't code at all. With improved detection technologies and computing power, researchers discovered extensive transcription occurring in the supposedly "junk" 98% of our genome. These non-protein-coding RNAs (ncRNAs) show reproducible, cell-specific expression patterns, particularly in brain regions.
The scientific community is finally recognizing ncRNAs as fully functional molecules, equal but different from proteins. Long ncRNAs like Xist and Tsix regulate X-chromosome inactivation, while others play critical roles in genomic imprinting. The Air ncRNA, expressed from the paternal chromosome, represses nearby genes by attracting epigenetic enzymes that create repressive histone modifications.
When miRNAs bind to mRNAs, they recognize specific sequences in the 3' UTR (untranslated region) that doesn't code for protein but remains in mature mRNA. This binding occurs through base-pairing, with positions 2-8 on the miRNA being crucial. If the match is imperfect, translation is prevented; if perfect, the mRNA is destroyed. A single miRNA can regulate multiple mRNAs, making their effects complex and cell-type dependent.
Evolution favors using ncRNAs for cellular regulation because altering proteins is risky-most proteins are already optimized through billions of years of evolution. Instead, complex organisms evolved by changing protein regulation through ncRNA networks. miRNAs play crucial roles in stem cell biology: the let-7 family helps embryonic stem cells differentiate, while other miRNAs help maintain pluripotency.
The impact of ncRNA disruption is becoming clearer in clinical conditions. In Tourette's syndrome, two unrelated patients shared the same single base change in the SLITRK1 gene's 3' UTR, creating a binding site for miR-189 that may abnormally down-regulate this neuronal development gene. In cancer, approximately 70% of chronic lymphocytic leukemia cases have lost miR-15a and miR-16-1, while the miR-17-92 cluster is over-expressed in various cancers.
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Epigenetics in Disease and Treatment
Epigenetic cancer treatments emerged not from logical progression but from chance observations properly interpreted. In the early 1970s, South African scientist Peter Jones was working with 5-azacytidine, a compound already known to have anti-cancer effects in leukemia. While testing its effects on mammalian cell lines, Jones observed something unusual: rather than discarding a culture flask with what appeared to be mold contamination, his closer examination revealed muscle fibers that occasionally twitched.
Further research confirmed 5-azacytidine inhibits DNA methylation by replacing cytidine with an abnormal base that cannot be methylated. This compound works because it contains a nitrogen atom where cytosine normally has a carbon atom, preventing DNA methyltransferases from adding methyl groups. When dividing cells are treated with this compound, the abnormal base gets incorporated into newly synthesized DNA, causing DNA methylation to progressively decrease.
In 1971, scientist Charlotte Friend discovered that dimethyl sulfoxide (DMSO) caused leukemia cells to turn red by activating the hemoglobin gene. Building on this observation, researchers eventually created SAHA (suberoylanilide hydroxamic acid), which effectively stopped cancer cell growth by inhibiting histone deacetylases (HDACs).
Though 5-azacytidine and SAHA target different epigenetic enzymes, their effects converge on a common outcome: increased gene expression. DNA methylation at CpG islands represses gene expression, so inhibiting DNMTs drives expression up. Similarly, histone acetylation promotes gene expression, so blocking HDACs prevents removal of acetyl groups, also increasing expression.
Cancer results from uncontrolled cell proliferation due to imbalances between proto-oncogenes and tumor suppressors. Beyond genetic mutations, we now recognize that tumor suppressors can be silenced epigenetically through DNA methylation or repressive histone modifications. Stephen Baylin's lab identified this phenomenon in kidney cancer, where hypermethylation of the VHL gene's CpG island switched off this tumor suppressor in 19% of cases.
The discovery that tumor suppressors are often silenced by epigenetic mechanisms has generated excitement because it offers a new treatment approach. Unlike mutations that permanently alter DNA, epigenetic silencing can potentially be reversed. Four epigenetic drugs have received FDA approval: two DNMT inhibitors (5-azacytidine/Vidaza and 2-aza-5'-deoxycytidine/Dacogen) and two HDAC inhibitors (SAHA/Zolinza and romidepsin/Istodax).
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The Epigenetics of Mental Health
Childhood trauma creates lasting impacts well into adulthood-abused children face three times higher suicide risk, 50% greater depression risk, and increased vulnerability to numerous psychiatric disorders. This persistent effect resembles epigenetic mechanisms, where triggering events continue influencing biology long after the trigger disappears.
Scientists now hypothesize that early trauma causes epigenetically-maintained alterations in brain gene expression, predisposing adults to mental illness. Central to this process is cortisol, a stress hormone produced by the adrenal glands. Adults who experienced childhood trauma show chronically elevated cortisol levels even when otherwise healthy, indicating persistently high stress levels.
Animal models reveal how early nurturing affects stress responses. Rat pups who receive more maternal licking and grooming during their first week develop into calmer adults with lower stress responses. The key molecular factor is increased expression of the cortisol receptor in the hippocampus of well-nurtured rats, which enables efficient negative feedback control of stress responses. This occurs through epigenetic changes-maternal licking triggers serotonin production, activating enzymes that decrease DNA methylation of the cortisol receptor gene, permanently increasing its expression.
Human studies support findings from rodent models. Professor Michael Meaney's team found that suicide victims with histories of childhood abuse showed higher DNA methylation at the cortisol receptor gene in their hippocampus compared to suicide victims without traumatic childhoods.
Evidence supporting epigenetics in stress responses continues to emerge. When naturally jumpy mice were treated with SAHA, a histone deacetylase inhibitor, the drug increased acetylation at the Gdnf promoter, boosting gene expression and transforming anxious mice into relaxed ones. Similarly, when "unloved" rat pups received TSA (another HDAC inhibitor), they grew up less stressed, with decreased DNA methylation at the cortisol receptor gene, improving stress regulation.
Memory formation's complexity makes experimental design challenging, but researchers have confirmed that both DNA methylation and histone modifications play crucial roles in memory and learning. Studies show that DNA methyltransferases increase in the rat hippocampus during learning, while inhibiting these enzymes blocks memory formation. Environmental enrichment increases histone acetylation in mice brains and improves memory, especially when combined with SAHA treatment.
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The Future of Epigenetics
The effects of nutrition on health and lifespan can be dramatic, with calorie restriction extending mammalian lifespan by up to one-third. But nature offers an even more remarkable example: honeybees, where diet determines whether genetically identical larvae develop into workers with weeks-long lifespans or queens that live twenty times longer.
Honeybee development represents a perfect example of epigenetics in action. When researchers sequenced the honeybee genome in 2006, they discovered DNA methyltransferase genes similar to those in vertebrates. Dr. Ryszard Maleszka's lab demonstrated that knocking down the Dnmt3 methyltransferase in larvae produced the same effect as feeding royal jelly-most larvae developed into queens rather than workers. Additionally, royal jelly contains compounds like phenyl butyrate and 10-hydroxy-2-decenoic acid (10HDA) that inhibit histone deacetylases, similar to the cancer drug SAHA.
By 2016, at least one Nobel Prize for Physiology or Medicine will likely be awarded to epigenetics researchers. Mary Lyon's work on X inactivation, John Gurdon and Shinya Yamanaka's cellular reprogramming research, and David Allis's studies of histone modifications all represent Nobel-worthy contributions to the field.
Peter Jones has pioneered epigenetic therapies, with histone deacetylase inhibitors and DNA methyltransferase inhibitors leading clinical trials, primarily for cancer but expanding to conditions like Huntington's disease. The most exciting developments involve drugs targeting specific epigenetic enzymes that modify particular amino acid positions on histone proteins.
Nutrition will become increasingly important in epigenetics research. Folic acid, which helps prevent spina bifida, is required for producing SAM, the molecule that donates methyl groups for DNA methylation. Dietary histone deacetylase inhibitors like sodium butyrate in cheese, sulforaphane in broccoli, and diallyl disulfide in garlic may help prevent cancer.
Epigenetic mechanisms will continue appearing in unexpected areas, like circadian rhythms. Many epigenetic enzymes likely have dual functions, modifying not just chromatin but other cellular proteins. Understanding these processes may require shifting from two-dimensional to three-dimensional thinking about the genome-seeing how regions fold and interact rather than viewing DNA as a linear script. Despite inevitable wrong turns and overpromising, the epigenetics revolution is underway and will help answer biology's most important questions in the coming decade.
