Epigenetics deals with heritable molecular traits whose basis is not the DNA sequence. The prefix epi- (Greek: επί ) indicates that modifications “on” the DNA are considered instead.
A distinction is made between the subfields of methylations and histone modifications (histones = proteins wrapped by DNA, whose “octamer” unit consists of two copies of the proteins H2A, H2B, H3 and H4).
The central DNA methylation in humans is that of the nucleic base cytosine in so-called CpG islands of DNA. In said islands, guanine bases are followed by cytosine bases (“CpG dinucleotide”). 75 % of the CpG islands are methylated.
The effect of the methylations is mediated by methyl-binding proteins. These cause a closing of the nucleosome conformation (nucleosome = unit of DNA and a histone octamer). Consequently, methylated sites are much more difficult to access by transcription factors (TPFs; proteins that attach to DNA and act on transcription).
Depending on the location of the methylations, they have a transcription-inhibiting (transcription = transcription of DNA into RNA) or transcription-enhancing effect. Methylation is catalyzed by various DNA methyltransferases – demethylation by demethylases.
Methylation is considered to be the evolutionary oldest function in the sense of a permanent silencing of a large part of the transposons (DNA elements that can change their locus (location), whereby the removal or new addition of these elements can lead to mutation events of a potentially pathological nature).
If these methylations are located at promoter regions (section on DNA that regulates the expression of a gene), the accumulation of specific TPFs is significantly reduced. Transcription of the DNA segment is thus not possible.
Methylations at enhancer sequences (non-transcribed gene sequences) prevent the attachment of transcription-enhancing TPFs. Methylations at non-regulatory sequences reduce the transcription rate due to low binding affinity of DNA polymerase to DNA.
Only methylations at silencer sequences (DNA sequences near the genes to which so-called repressors (blocks the binding of RNA polymerase to the promoter) can bind) of DNA can contribute to the increase of transcriptional activity, because they prevent the attachment of transcription-inhibiting factors.
Histone modifications are characterized by the addition of a variety of chemical groups to the side chains of the amino acids of histone proteins. The most common of these are acetylations and methylations. Acetylation affects only the amino acid lysine and results in neutralization of the positively charged lysine. The interactions with the negatively charged DNA decrease, leading to a loosening, i.e. decrease in compaction, of the histone-DNA complex. The result is increased accessibility of transcription factors.
Histone methylations also affect the degree of compaction of the nucleosome conformation. Here, however, it depends on amino acids or histone proteins whether opening or compaction occurs.
Another special feature is the presence of a histone code. The “succession” of different histone modifications ultimately leads to the recruitment of so-called chromatin modeling factors – depending on the type, these proteins increase or decrease the degree of condensation of the nucleosome confirmation.
Therapy (perspective): Since the optimal methylation pattern of cells and cell types is largely unknown, and thus only minor statements can be made about the most ideal protein ratio of the cell, but also the histone code is only fragmentally determined, therapeutic modifications are currently not useful.
In the future, however, upregulation and downregulation of genes may be useful in the treatment of diseases such as tumors, mental disorders, and autoimmune diseases, as well as in the anti-aging sector.
