A Quick Guide to Epigenetics

By Elaine Guevara

Elaine Guevara
Elaine Guevara
May 03, 2018

Recently, I’ve spent time at the National Museum of Natural History engaging with the public about my dissertation research on comparative primate epigenetics. Epigenetics has received a lot of attention in the media, so most adults have heard of epigenetics. Many are aware that it’s a hot new field of scientific inquiry and some may even have a sense that it is explaining everything genetics couldn’t, reconciling nature and nature, giving us more reasons to blame our parents (and grandparents) for our problems, etc.

But what is it, really, and what is it not? And is there a real reason to care? As is so often the case, the more hype there is about something (e.g., Bitcoin, the Higgs boson, antioxidants), the more difficult it can be to get a grasp on what is really going on with that thing.

What is epigenetics?

Although there is long-standing disagreement about how epigenetics should best be defined [i], I like to define epigenetics as inherited chemical alterations to DNA that do not change the underlying DNA sequence. For example, DNA methylation (or often simply “methylation”) is the best characterized epigenetic “mark” (or chemical alteration). It involves the addition of a methyl group to one of the carbons making up the nucleotide base cytosine (C).

The other major type of epigenetic mark is a group of changes called histone modifications that comprise an array of different small chemical groups that get added to many different parts of the histone proteins that DNA wraps around. Histone mods are quite complex; knowing they exist is great for now.

Gene of a human compared to a chimpanzee


But what does it do?

Epigenetic marks can modify gene expression. In particular, they are important for maintaining cellular identity (i.e. whether a cell is a fibroblast, neuron, white blood cell, etc.). Remember that all the cells in our body have the same DNA cookbook (genome). Which recipes are cooked and in what quantity (gene expression) results in different cell types having different functions.

During development, cellular differentiation is achieved as epigenetic marks, including methylation, get laid down across the genome in a species- and cell-type-specific manner. Exactly how methylation gets patterned, at least in some regions of the genome, can be sensitive to environmental inputs, like nutritional intake. After this intense period of prenatal genome methylating, methylation levels at some genomic loci can continue to shift over the lifespan, sometimes also in response to the environment.

As for how methylation influences gene expression, current thinking holds that most of the time DNA methylation decreases expression of nearby genes. The presence of methylated Cs appears to block the factors that cluster near the start of a gene sequence to begin the process of transcribing the gene to mRNA. But the more we learn about methylation, the more it is clear that its effect is entirely context dependent. For example, methylation within particular sites may instead block factors that prevent transcription and so, in a “double negative”-type scenario, methylation ends up promoting expression of the nearby gene. Similarly, methylation of Cs in exons may also boost expression[ii].


When people realized that epigenetic marks seem to both be acquired during the lifespan and heritable, the inevitable question arose of whether Jean-Baptiste Lamarck hadn’t been at least partly correct in his assessment of the nature of inheritance all along [iii],[iv],[v]. The short answer is yes. And no.

At this point, it seems that at least in mammals, epigenetic modifications primarily enable plasticity within an organism’s lifetime rather than across generations [vi]. Part of the confusion on this point may come from the use of the word inherit. Although I defined epigenetic marks as inherited, I meant across cell divisions within an individual, not that they are necessarily inherited from one generation to the next. In fact, most epigenetic marks are scrubbed clean from parental genomes before they are passed down to offspring in a two-step process called germline reprogramming. First, most methylation is removed from the haploid genomes of gametes and then, again, from the zygote’s genome post-fertilization. This reset is what allows for the correct, species-specific process of embryonic differentiation to unfold [vi].

Instead, most examples of putative “transgenerational” epigenetic inheritance seem to be explainable by maternal effects, meaning that particular gestational conditions (e.g., energy balance) that are likely to be correlated with a mother’s own epigenetic profile can promote the embryo acquiring a similar epigenetic profile [vi]. But there are a few special cases, most notably, in the case of transposable elements (“jumping genes”) and other repetitive loci, including some imprinted genes, where the parental methylation pattern may be reinstated after gamete programming and maintained by special factors through the second round of reprogramming post-fertilization [vi]. These exceptions to the rule are generally considered to promote genome stability during development and, while interesting, have probably been unduly focused on.

Nevertheless, Lamarck can be considered vindicated. He was on the mark when it came to his subject of botany, as it is now clear that acquired epigenetic profiles are commonly inherited transgenerationally in plants, which may be related to clonal reproduction [vi].

Plasticity or programming?

So, we now understand that for the most part in mammals, epigenetics seems to contribute far more to individual plasticity than transgenerational programming. But at the same time epigenetics is largely about species-specific developmental programming. And, in fact, many of the best examples of said individual plasticity in response to environmental effects involve exposure early in life that appears to produce fairly stable, lifelong phenotypes. These observations raise one of the major outstanding questions related to epigenetics: to what degree is epigenetics primarily a mechanism for developmental and early life programming, with some critical periods for environmental input, versus a source of phenotypic plasticity throughout adulthood? Although it is clear that there is epigenetic change throughout life [vii], it remains less clear, for example, whether some physiological pathways or cell types retain more plasticity than others or to what degree diminishing epigenetic responsiveness might characterize aging.

What does it have to do with human evolution?

In 1975, Mary-Claire King and Alan Wilson [viii] published a seminal paper in molecular anthropology arguing that differences in protein sequences could not account for the phenotypic differences observed between humans and chimpanzees. They proposed instead that these differences were the result of divergent patterns of gene expression during development, intuiting that subtle differences at the right time could yield vast differences in adult form. Coincidentally, in the same year, two foundational papers proposed that DNA methylation could produce differences in gene expression patterns in the absence of DNA sequence divergence [ix],[x].

As it turned out, epigenetics does regulate gene expression during development and so almost certainly underlies many species differences in phenotype. Although it is difficult to study developmental processes, researchers have identified species-specific patterns of methylation in the same types of cells in humans and chimpanzees, which could provide clues to the molecular basis of phenotypes unique to our lineage [xi],[xii].

Another gene silenced cartoon


Want to learn more?

In addition to the references below, check out the thorough and exceptionally readable book The Epigenetics Revolution by Nessa Carey.

[i] Thayer ZM, Non AL. 2015. Anthropology meets epigenetics: Current and future directions. American Anthropologist 117:722-35.

[ii] Jones PA. 2012. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nature Reviews Genetics 13: 484-492.

[iii] Jablonka E, Lamb MJ. 1999. Epigenetic inheritance and evolution: the Lamarckian dimension. Oxford University Press.

[iv] Skinner MK. 2015. Environmental epigenetics and a unified theory of the molecular aspects of evolution: a neo-Lamarckian concept that facilitates neo-Darwinian evolution. Genome Biology and Evolution 7:1296-302.

[v] Whitelaw E. 2015. Disputing Lamarckian epigenetic inheritance in mammals. Genome Biology 16:60.

[vi] Heard E, Martienssen RA. 2014. Transgenerational epigenetic inheritance: myths and mechanisms. Cell 157:95-109.

[vii] Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suñer D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M. 2005. Epigenetic differences arise during the lifetime of monozygotic twins. Proceedings of the National Academy of Sciences of the United States of America 102:10604-10609.

[viii] King MC, Wilson AC. 1975. Evolution at two levels in humans and chimpanzees. Science 188:107-116.

[ix] Riggs AD. 1975. X inactivation, differentiation, and DNA methylation. Cytogenetic and Genome Research 14:9-25.

[x] Holliday R, Pugh JE. 1975. DNA modification mechanisms and gene activity during development. Science 187:226-232.

[xi] Pai AA, Bell JT, Marioni JC, Pritchard JK, Gilad Y. 2011. A genome-wide study of DNA methylation patterns and gene expression levels in multiple human and chimpanzee tissues. PLoS Genetics 7:e1001316.

[xii] Hernando-Herraez I, Prado-Martinez J, Garg P, Fernandez-Callejo M, Heyn H, Hvilsom C, Navarro A, Esteller M, Sharp AJ, Marques-Bonet T. 2013. Dynamics of DNA methylation in recent human and great ape evolution. PLoS Genetics 9:e1003763.

Cartoon "Another gene silenced"