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In biology, the epigenome of an organism is the collection of chemical changes to its DNA and histone proteins that affects when, where, and how the DNA is gene expression; these changes can be passed down to an organism's offspring via transgenerational epigenetic inheritance. Changes to the epigenome can result in changes to the structure of chromatin and changes to the function of the genome. The human epigenome, including DNA methylation and histone modification, is maintained through cell division (both mitosis and meiosis). The epigenome is essential for normal development and cellular differentiation, enabling cells with the same genetic code to perform different functions. The human epigenome is dynamic and can be influenced by environmental factors such as diet, stress, and .
The epigenome is involved in regulating gene expression, development, tissue differentiation, and suppression of transposable elements. Unlike the underlying genome, which remains largely static within an individual, the epigenome can be dynamically altered by environmental conditions.
DNA functionally interacts with a variety of epigenetic marks, such as cytosine methylation, also known as 5-methylcytosine (5mC). 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.
Individuals differ with their epigenetic profile, for example the variance in CpG site methylation among individuals is about 42%. On the contrary, epigenetic profile (including methylation profile) of each individual is constant over the course of a year, reflecting the constancy of our phenotype and metabolic traits. Methylation profile, in particular, is quite stable in a 12-month period and appears to change more over decades.
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. These regions tend to occur in clusters and the two genomic areas of high CoRSIV density are observed at the major histocompatibility (MHC) locus on chromosome 6 and at the pericentromeric region on the long arm of chromosome 20.
CoRSIVs are enriched in intergenic and quiescent regions (e.g. Subtelomere regions) and contain many transposable elements, but few CpG islands (CGI) and transcription factor binding sites. CoRSIVs are under-represented in the proximity of genes, in Heterochromatin regions, active promoters, and enhancers. They are also usually not present in highly conserved genomic regions.
CoRSIVs can have a useful application: measurements of CoRSIV methylation in one tissue can provide some information about epigenetic regulation in other tissues, indeed we can predict the expression of associated genes because systemic epigenetic variants are generally consistent in all tissues and cell types.
Anyway, differential expression concerns only a slight number of methylated genes: only one fifth of genes with CpG methylation shows variable expression according to their methylation state. It is important to notice that methylation is not the only factor affecting gene regulation.
The percentage of DNA methylation is different in and in sperm: the mature oocyte has an intermediate level of DNA methylation (72%), instead the sperm has high level of DNA methylation (86%). Demethylation in paternal genome occurs quickly after fertilisation, whereas the maternal genome is quite resistant at the demethylation process at this stage. Maternal different methylated regions (DMRs) are more resistant to the preimplantation demethylation wave.
CpG methylation is similar in germinal vesicle (GV) stage, intermediate metaphase I (MI) stage and mature metaphase II (MII) stage. Non-CpG methylation continues to accumulate in these stages.
Chromatin accessibility in germline was evaluated by different approaches, like scATAC-seq and sciATAC-seq, scCOOL-seq, scNOMe-seq and scDNase-Seq. Stage-specific proximal and distal regions with accessible chromatin regions were identified. Global chromatin accessibility is found to gradually decrease from the zygote to the 8-cell stage and then increase. Parental allele-specific analysis shows that paternal genome becomes more open than the maternal genome from the late zygote stage to the 4-cell stage, which may reflect decondensation of the paternal genome with replacement of by .
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. Only rare genetic variants show the stochastic type of gene regulation.
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. 36 cell and tissue types from 13 participant donors were used to examine 71 epigenomes. The results of WGBS tested on 49 methylomes revealed CpG methylation imbalances exceeding 30% differences in 5% of the loci. The stochastic switching occurred at thousands of heterozygous regulatory loci that were bound to transcription factors. The intermediate methylation state is referred to the relative frequencies between methylated and unmethylated epialleles. The epiallele frequency variations are correlated with the allele affinity for transcription factors.
The analysis of the study suggests that human epigenome in average covers approximately 200 adverse SD-ASM variants. The sensitivity of the genes with tissue-specific expression patterns gives the opportunity for the evolutionary innovation in gene regulation.
Haplotype reconstruction strategy is used to trace chromatin chemical modifications (using ChIP-seq) in a variety of human tissues. Haplotype-resolved epigenomic maps can trace allelic biases in chromatin configuration. A substantial variation among different tissues and individuals is observed. This allows the deeper understanding of cis-regulatory relationships between genes and control sequences.
The epigenetic profiles of human tissues reveals the following distinct histone modifications in different functional areas:
| H3K4me3 | H3K4me1 | H3K36me3 | H3K27me3 |
| H3K27ac | H3K27ac | H3K9me3 |
The structural modifications that these projects aim to study can be divided into five main groups:
Topological domains in humans, like in other mammalians, have many functions regarding gene expression and transcriptional control process. Inside these domains, the chromatin shows to be well tangled, while in the boundary regions chromatin interactions are far less present. These boundary areas in particular show some peculiarity that determine the functions of all the topological domains.
Firstly, they contain insulator regions and barrier elements, both of which function as inhibitors of further transcription from the RNA polymerase enzyme. Such elements are characterized by the massive presence of insulator binding proteins CTCF.
Secondly, boundary regions block heterochromatin spreading, thus preventing the loss of useful genetic informations. This information derives from the observation that the heterochromatin mark H3K9me3 sequences clearly interrupts near boundary sequences.
Thirdly, transcription start sites (TSS), housekeeping genes and Transfer RNA genes are particularly abundant in boundary regions, denoting that those areas have a prolific transcriptional activity, thanks to their structural characteristics, different from other topological regions.
Finally, in the border areas of the topological domains and their surroundings there is an enrichment of Alu element/B1 and B2 SINE . In the recent years, those sequences were referred to alter binding site of CTCF, thus interfering with expression of some genomic areas.
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.
Hi-C 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.
This kind of studies are currently limited by the lack or unavailability of raw data.
An international effort to assay reference epigenomes commenced in 2010 in the form of the International Human Epigenome Consortium (IHEC). "BioNews - Human Epigenome project launched" . IHEC members aim to generate at least 1,000 reference (baseline) human epigenomes from different types of normal and disease-related human cell types. "France: Human epigenome consortium takes first steps" . 5 March 2010.Eurice GmbH. "About IHEC".
Reference epigenomes for healthy individuals will enable the second goal of the Roadmap Epigenomics Project, which is to examine epigenomic differences that occur in disease states such as Alzheimer's disease.
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