Epigenome
[1] The human epigenome, including DNA methylation and histone modification, is maintained through cell division (both mitosis and meiosis).
[2] The epigenome is essential for normal development and cellular differentiation, enabling cells with the same genetic code to perform different functions.
Unlike the underlying genome, which remains largely static within an individual, the epigenome can be dynamically altered by environmental conditions.
The main types of epigenetic changes include:[3] Addition of a methyl group to the DNA molecule, typically at cytosine bases.
This epigenetic mark is widely conserved and plays major roles in the regulation of gene expression, in the silencing of transposable elements and repeat sequences.
[6] Most of the CoRSIVs are only 200 – 300 bp long and include 5–10 CpG dinucleotides, the largest span several kb and involve hundreds of CpGs.
[7] Quantification of the heritable basis underlying population epigenomic variation is also important to delineate its cis- and trans-regulatory architecture.
In particular, most studies state that inter-individual differences in DNA methylation are mainly determined by cis-regulatory sequence polymorphisms, probably involving mutations in TFBSs (Transcription Factor Binding Sites) with downstream consequences on local chromatin environment.
If trans-acting variants do exist in human populations, they probably segregate as rare alleles or originate from somatic mutations and present with clinical phenotypes, as is the case in many cancers.
The results of WGBS tested on 49 methylomes revealed CpG methylation imbalances exceeding 30% differences in 5% of the loci.
[9] On the sites of gene regulatory loci bound by transcription factors the random switching between methylated and unmethylated states of DNA was observed.
This is also referred as stochastic switching and it is linked to selective buffering of gene regulatory circuit against mutations and genetic diseases.
The study made by Onuchic et al. was aimed to construct the maps of allelic imbalances in DNA methylation, gene transcription, and also of histone modifications.
These modifications can either activate or repress gene expression by altering chromatin structure and accessibility of the DNA to transcriptional machinery.
These RNA molecules can modulate gene expression by various mechanisms, including mRNA degradation, inhibition of translation, and chromatin remodeling.
In the recent years, those sequences were referred to alter binding site of CTCF, thus interfering with expression of some genomic areas.
[19] Further proofs towards a role in genetic modulation and transcription regulation refers to the great conservation of the boundary pattern across mammalian evolution, with a dynamic range of small diversities inside different cell types, suggesting that these topological domains take part in cell-type specific regulatory events.
[14] The 4D Nucleome project aims to realize a 3D maps of mammalian genomes in order to develop predictive models to correlate epigenomic modifications with genetic variation.
In particular the goal is to link genetic and epigenomic modifications with the enhancers and promoters which they interact with in three-dimensional space, thus discovering gene-set interactomes and pathways as new candidates for functional analysis and therapeutic targeting.
Hi-C [20] is an experimental method used to map the connections between DNA fragments in three-dimensional space on a genome-wide scale.
This technique combines chemical crosslinking of chromatin with restriction enzyme digestion and next-generation DNA sequencing.
[22] In recent decades, evidence has accumulated supporting the additional idea that DNA damage and repair elicit widespread epigenome alterations that also contribute to aging (e.g.[23][24]).
