Epigenetics 201: the four ‘R’s

Want to know a little more about epigenetic marks; what they are and how they come about? Read on.

Epigenetic marks are all small molecules, some examples being the methyl group (-CH3) and the acetyl group (-COH3). Many different marks can bind to histones – the proteins that are responsible for packaging DNA into the two metres of genetic information found in every nucleus. Histones are shaped like commas and most epigenetic marks bind to the tail of the comma. However, only a single mark – the methyl group – binds to DNA and only then, to one specific sequence – cytosine-guanine (CG) – often referred to as CpG, the ‘p’ denoting the phosphate ‘backbone’ of the DNA double helix. Together with other packaging molecules and RNA, they make a substance called chromatin. Chromatin can come in many flavours depending on how tight it is packed, from ‘open for business’ to ‘closed for the season’ and states in between. At any particular gene, combinations of different epigenetic marks combine to influence its structure and function. Generally speaking, when regions regulating gene activity contain DNA with CpG methylation, the gene is inactive. Conversely, if the CpG methylation is removed, the gene may be activated. This is, however, a very simplistic interpretation because it ignores all the other epigenetic marks but it fits most situations.

NIHepi2

How do epigenetic marks get added and removed from our genes? This is when the ‘four Rs’ come in: epigenetic Recruiters, wRiters, Readers and eRasers. In the figure below, a strand of DNA located at a gene’s control region is illustrated with, for clarity, only four groups of histones.

JC1The first stage of epigenetic change involves the addition of sequence-specific Recruiter proteins or RNA, illustrated by the coloured symbols.

JC2Next, epigenetic wRiters, often called transferases, attracted by the recruiters, add an epigenetic mark, for example, acetyl (Ac), methyl (Me) and phosphoryl (P). Note that the first three marks are added to histones and the final, methyl mark, is added to DNA.

JC3Next, a combination of epigenetic Readers specific for each epigenetic mark bind in tandem in a way analogous to a key in a lock. Each gene or group of genes can have its own specific combination of marks, writers and readers.

JC4This ‘opening of a lock’ is akin to opening up the structure of the gene for it to be expressed.

JC5To reverse this process, a set of molecular eRasers specific for each mark can strip the mark off. An example of such an eraser is the deacteylase group of proteins.

JC6Which, when all marks have been stripped off, brings the gene back to square one.

JC7Further links and a more basic description of epigenetics can be found in my Blog “Epigenetics: from Greeks to geeks and leaks”

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