“Changes in the way genes are expressed that occur without changes in the sequence of nucleic acids,” is how “epigenetics” is defined in Taber’s Cyclopedic Medical Dictionary (2017), and that’s about the clearest definition I’ve come across. Another definition, formulated at a Cold Spring Harbor meeting twelve years ago, is a “stably heritable phenotype resulting in a chromosome without alternations in the DNA sequence.”  The term was introduced in 1942 by an embryologist named Conrad Waddington to refer to the complex of developmental processes between the genotype and phenotype. In its broadest sense, it can be used to describe anything other than DNA sequence that influences the development of the organism. Epigenetic changes can switch genes on or off and determine which proteins are transcribed. For example, such “silencing” might explain, in part, why genetic twins are not phenotypically identical.

Intracellularly, there are three interactive systems that can silence cells: DNA methylation, histone modifications, and RNA-associated silencing.

DNA methylation is an epigenetic mechanism that occurs by the addition of a methyl (CH3) group to DNA, thereby often modifying the function of the genes and affecting gene expression. (DNA de-methylation is necessary for epigenetic reprogramming of genes and is also directly involved in many important disease mechanisms such as tumor progression.) Histones are primary protein components of eukaryotic chromatin. Some histones have tails protruding from the nucleosome that can be modified post-translationally to alter the histone’s interactions with DNA and nuclear proteins, leading to epigenetic changes for regulating many normal and disease-related processes.

Genes can also be turned off by RNA when it is in the form of antisense transcripts, noncoding RNAs, or RNA interference. RNA might affect gene expression by causing heterochromatin to form or by triggering histone modification and DNA methylation.

There are numerous subfields of epigenetics. Three worth noting are computational, behavioral, and forensic. Computational EG uses bioinformatic methids to complement experimental research. Prediction algorithms build statistical models of epigenetic information from training data and can therefore act as a first step toward quantitative modeling of a mechanism. An interesting emerging topic is that of “regulatory epigenetic circuitry”, I.e., reverse-engineering the regulatory networks that read, write, and execute EG codes. Behavioral epigenetics seeks to explain how nurture shapes nature, to understand how the expression of genes is influenced by experiences and the environment to produce individual differences in behavior, cognition, , personality and mental health. Epigenetic changes can influence the growth of neurons in the developing brain as well as modify activity of the neurons in the adult brain, thus influencing the organism’s behavior.

The forensic application refers, of course, to solving crimes. As noted, the methylation of DNA is a major form of epigenetics. Current methods to fabricate DNA usually exclude important methylation marks found in biological tissues, making this a way to confirm the identity of an individual when evidence is being assessed. There is evidence for specific methylation sites to be associated with the circadian clock, meaning a sample could have a time of day associated with their death through methylation marks.

While epigenetics is a legitimate field of scientific investigation, it is sometimes exploited by perpetrators of pseudoscience who propose excessive, unsustainable claims. As elsewhere, consumers of information must use critical thinking in addition to reliable knowledge to detect dubious assertions.

Epigenetic changes are relevant to the development of certain diseases, most notably, cancer. Hypermethylation can lead to the instability of microsatellites, which are reoeated sequences of DNA. Microsatellite instability has been linked to many cancers, including colorectal, endometrial, ovarian, and gastric. Drugs used to combat cancerous changes in both DNA methylation and histone modification are currently in use. Some recent research suggests that a regimen combining both epigenetic and immunotherapy may be more effective than each by itself. Numerous clinical trials are currently investigating the potential of this combination.

Rylan Dray, PhD – March 2020