Epigenetic modification has emerged as a surrogate marker of exposure to the environment. Along with environmental exposure data and genetic variants, they are now an important component of epidemiology research that help to identify disease-relevant genomic areas, offer options for prevention and early detection measures, and improve risk stratification.
Any meiotic or mitotic alteration that does not result in a change in DNA sequence but has a major impact on the organism’s development is characterised as an epigenetic modification.
In vertebrates, enzyme modifications of cytosine bases and histone proteins in the nucleosome core give heritable epigenetic information not encoded in the cell’s nucleotide sequence. During the S phase of the cell cycle, chromatin replication provides a window of opportunity for these enzymes and auxiliary factors to load onto newly produced DNA and robustly disseminate all the molecular information.
If the correct epigenetic modification is not preserved it could have disastrous outcomes for the cell, such as improper gene expression and apoptosis. Notably, the methylation of cytosine in mammalian cells is maintained reliably between cell divisions. DNA (cytosine-5) methyltransferases catalyse the retention of DNA methylation throughout cell division (DNMTs).
DNA Methylation and Epigenetic Modification
DNA methylation occurs in mammalian genomes by covalent alteration of the fifth carbon (C5) in the cytosine base, with the majority of these modifications occurring at CpG dinucleotides. CpG dinucleotides are widely dispersed across the human genome, although they are concentrated in dense regions known as CpG islands (CGIs). The methylation pattern in every particular cell is the result of separate yet dynamic methylation and demethylation processes. Methylation patterns in differentiated somatic cells are generally permanent and inheritable in the mammalian genome.
However, methylation pattern modification (demethylation/remethylation) occurs in two developmental stages: germ cells and preimplantation embryos. Unlike primordial germ cells, where genome-wide demethylation occurs, the genomes of mature sperms and eggs in mammals are extensively methylated as compared to somatic cells.
During development and in normal (non-neoplastic/non-senescent) tissue types, CpG dinucleotides within CGI promoters are normally unmethylated. During development and in normal (non-neoplastic/non-senescent) tissue types, CpG dinucleotides within CGI promoters are normally unmethylated.
In a study CGIs showed tissue-specific methylation of development-related genes, implying a pre-programmed DNA methylation process. Another way for DNA methylation to spread is by methylation spreading, which begins immediately after fertilisation with genome-wide demethylation. The majority of the genome is remethylated after the blastocyst stage and continues at a lesser rate throughout development.
The methylation status of CGIs was shown to be connected with DNA sequence, repeat rates, and projected DNA structures, according to combined research using bioinformatic techniques and methylation data from chromosome 21.
One of the fundamental aspects linked with complicated disorders such as cancer, type 2 diabetes, schizophrenia, and autoimmune disease is aberrant gene expression. These disorders are known to be heritable, even though their inheritance patterns are not Mendelian. Several lines of evidence imply that epigenetic abnormalities, in combination with genetic modifications, are to blame for the illnesses’ dysregulation of important regulator genes. The epigenetic process explains some of the characteristics of complicated diseases, such as late start, gender effects, parent-of-origin effects, and symptom variation.
Mammalian diploid animals have two copies of autosomal genes, one from each parent. Both paternal alleles have an equal chance of being expressed in cells in most circumstances. However, depending on the gene’s parent-of-origin, a minority of autosomal genes are prone to genomic imprinting, in which expression is restricted to one of two parental alleles.
Failure to establish accurate genomic imprinting has been found to cause problems in embryonic and neonatal development, as well as neurological illnesses such as Prader-Willi syndrome, in placental mammals. Several protein-coding genes and at least one non-coding RNA (ncRNA) gene are often found in each imprinted gene cluster, which spans 100–3000 kb of DNA. The imprinting control region (ICR) is a single main cis-acting element that regulates the expression of imprinted genes in each cluster. ICRs are CpG-rich DNA regions that are solely methylated in one of the two parental gametes, carrying the parental information. During gametogenesis, this DNA methylation imprint is acquired. The parental imprints are determined before the sex is determined.
Gametic imprints are placed on paternally imprinted genes during sperm production and maternally imprinted genes during egg development as the embryo develops into a male or female. This methylation imprint is retained on the same parental chromosome through cell divisions after fertilisation. A set of epigenetic machinery is required for the establishment and preservation of imprints.
Heterogametic species are known to have a different number of sex chromosomes than females. Males and females have distinct transcription levels for these chromosomes. Dosage compensation systems involving gene expression and chromatin accessibility regulations have arisen during evolution to address this imbalance.
The existence of an underlying epigenetic process that increases the accessibility of the X chromosome chromatin in males, allowing for X-linked gene dose correction between sexes has been suggested in many studies.
Dosage compensation is frequently regulated by epigenetic mechanisms that regulate chromatin accessibility on the X or Z chromosomes in humans and birds respectively.
Chromatin Modification and Epigenetics
Long-term gene expression is influenced by epigenetic mechanisms, which is necessary for the precise execution of developmental programmes and the maintenance of cell types across cell divisions.
In addition to the activation of genomic programmes that lead to the formation of specific cell types, a cell must also mute alternative gene expression programmes that are exclusive to other cell types to secure its fate. Neurogenesis, when neural cell fates are acquired in the developing nervous system, is the finest illustration of this lineage restriction.
In contrast to the stable and inheritable silencing of neuronal chromatin in terminally differentiated nonneuronal cells, the situation in ES cells and neuronal progenitors raises another epigenetic concern about gene expression, because these cells should be able to relieve the silent chromatin state upon differentiation to allow lineage-specific gene expression. Together, epigenetic mechanisms provide a key foundation for stem cell identity maintenance and long-term cellular memory, both of which are critical for normal development.