Photo by Brona McVittie
Epigenetic marks regulate the 'open' or 'closed' state for regions of the genome and thereby control the 'on' and 'off' status of genes. A key point is that epigenetic marks can be heritable and provide a means to transmit the 'on' or 'off' state through the process of cell division. Currently we know of three major players: RNA, the nucleosome and DNA methylation, the three pillars of epigenetics. These players talk with one another extensively providing a coordinated orchestration of gene switching essential for making a complex organism.
Best known for its role as the messenger, transferring genetic information from the DNA to protein manufacturing factories located outside the cell nucleus, RNA is increasingly recognised as a key player in the epigenetic story. At present we know about two types of 'epigenetic' RNA, very small RNAs, called small interfering (si) RNAs, and very big non-coding (nc) RNAs. The siRNAs are involved in establishing the 'closed' configuration at certain sites, notably in DNA repeats found at centromeres and elsewhere in the genome. As for the ncRNAs, some are involved in establishing an 'open' configuration in specific regions of the genome, whilst others function in establishing the 'closed' configuration either in specific regions or even over a whole chromosome. There are examples where transmitting the memory of the 'open' or 'closed' configuration through cell division requires the continuous production of one of these RNAs and in this respect the RNAs can be regarded as epigenetic marks.
There are four core histone proteins that form the nucleosome, a structure which is used to package the DNA in the nucleus. Histone proteins can be modified at a number of different sites by adding or taking away either small chemical groups, termed acetyl-, methyl-, and phosphate-, or larger 'protein' attachments, termed ubiquityl-. The effect of these modifications is to change the nature of the nucleosome in a manner that affects amongst other things how 'open' or 'closed' the chromatin is. There is evidence suggesting that specific combinations of histone modification can be read like a code, determining for example whether the associated gene should be on or off. This is thought to involve a set of factors that recognise and bind to a given modification present at a specific position on a specific histone. In addition to histone modifications there are a number of 'variant' histones, related to one of the four core histones but with specific properties, for example helping to make a nucleosome more 'open' or 'closed'. Finally there is the linker histone, termed H1, that has an important role in regulating how tightly nucleosomes are packaged. Histone modifications and histone variants are central players in epigenetic processes in all organisms.
DNA is made up of four different bases that represent the four letters of the genetic code, adenine, cytosine, guanine, and thymine. Sometimes the small chemical group termed methyl- is added to a base, conferring an extra level of information. In higher organisms (i.e not bacteria) methylation is largely confined to the base cytosine. Methylated cytosine is associated with formation of 'closed' chromatin and therefore with switching genes 'off'. This is thought to involve a set of factors that recognise and bind to the modified base. Cytosine methylation is thought to have first arisen as a 'defence' against invading DNA elements, termed transposons. It has since been co-opted as a mechanism for epigenetic gene regulation. An important feature of DNA methylation is that it can be faithfully copied during the process of DNA replication, i.e. when cells double their chromosomes in readiness for cell division. This provides a nice example of how epigenetic information is transmitted from one cell generation to the next. DNA methylation occurs in many, but not all, higher organisms."