Epigenetics is the study of heritable nonencoded genetic changes that turn genes on or off. Examples include activating changes such as histone acetylation and DNA demethylation, repressive changes like DNA methylation and histone modifications induced by noncoding RNAs, such as microRNA and long noncoding RNA (lncRNA). Epigenetic modifications can modulate gene expression and/or alter cellular signaling pathways, which may affect individual susceptibility to various diseases. For example, epigenetic changes have been associated with the development of fibrosis in pulmonary fibrosis and liver disease.
An Overview of Epigenetics
Epigenetic changes, in general, refer to stable and heritable modifications of chromatin—the DNA and its associated histone proteins—that are independent of the underlying DNA sequence and that help to determine the phenotypic traits of cells during development. The core unit of chromatin is the nucleosome, which consists of 147 bp of DNA folded around histone octamers containing two each of the histone proteins H2A, H2B, H3, and H4. Histone H2A and H3 are known to exist in multiple forms which differ in their primary amino acid sequence at a limited number of sites in the histone. Changes in chromatin structure allow (or forbid) specific multiprotein transcriptional regulator complexes to access DNA sequences. Such changes in chromatin structure are achieved chiefly by three distinct mechanisms: DNA methylation, histone modifications and ATP-dependent chromatin remodeling. Epigenetic modifications of chromatin have generally been considered to be both stable and heritable.
Figure 1. Major forms of epigenetic changes. (Trollope, A.F; et al. 2017)
Epigenetic mechanisms determine the way genes are organized in the cell nucleus and influence their expression by changing the conformation of the chromatin and therefore the accessibility of the DNA for transcription factors, other factors, and the transcriptional machinery. These epigenetic mechanisms include post-translational histone modifications (PTMs), DNA methylation, and non-coding RNAs, resulting in activation, silencing, or posing of genes and thereby regulating patterns of gene expression.
Epigenetics Signaling Pathway
Both the environment and individual lifestyle can interact with the genome to influence epigenetic change. Such as many psychological challenges or stress can induce epigenetic mechanism.
Psychological challenge activates N-methyl-d-aspartate (NMDA) receptor (NMDA-R) and glucocorticoid receptor (GR), resulting in the activation of the Ras-Raf-MEK-ERK signaling pathway, the phosphatidylinsoitil 3'-kinase-activated kinase (PI3K), protein kinase B/Akt, and the transcription factors such as Myc. Stresses activate receptor tyrosine kinases (RTK), cooperating with phosphorylation regulate the activators of the mitogen-activated protein (MAP) kinases Erk1/2 and MEK1/2. The glucocorticoid receptor (GR), predominant corticosterone in rodents, interacts with the ERK signaling pathway which drives phosphorylation and chromatin remodeling. The kinases ERK1 and ERK2 activate MSK1 and ETS transcription factor 1 (ELK1) through phosphorylation. Those signals subsequently regulate epigenetic modiﬁcations and gene transcriptional responses.
MSK1/2 is an H3S10 kinase, whereas Elk-1 can recruit the histone acetyl-transferase p300, which can acetylate histone H3 at various lysine residues. The activation of this histone kinase and histone acetyl-transferase leads to the formation of the combinatorial H3K9ac-S10p–K14ac histone marks within the promoter regions of the immediate-early genes Fos and Egr1, thereby facilitating the induction of gene transcription.
DNA methylation, the best known epigenetic signal, is associated with condensed and compacted chromatin. It is thought to have the opposite effect, allowing transcriptional activation. Three functional enzymes responsible for DNA methylation in mammals have been identified, namely DNA methyltransferase 1 (DNMT1), DNA methyltransferase 3A (DNMT3A), and DNA methyltransferase 3B (DNMT3B). DNMT in conjunction with the endogenous methyl donor SAM converts cytosine to 5′methyl-cytosine. After the methyl transfer reaction, SAM forms a byproduct, S-adenosyl homocysteine (SAH), which acts as a potent inhibitor of DNMT. DNA methylation typically occurs at cytosines that are followed by a guanine.
Figure 2. Schematic representation of DNA methylation. (Zakhari, S. 2013)
The Function of Epigenetics
Epigenetics plays an important role in affecting gene expression. Histone modifications determine the genome’s accessibility to transcription factors, while DNA methylation is influenced by post-translational modifications of histone proteins, such as acetylation, methylation, phosphorylation, ubiquitination, and crotonylation. Acetylation of specific histones and/or specific residues has been found to be associated with long-term memory formation. For example, after contextual fear conditioning, histone H3 but not H4 acetylation increased specifically within the CA1 region of the hippocampus. Importantly, it was found that activation of the NMDA-R/ERK1/2/MSK1/2-ELK1 signaling pathway is critical for the consolidation of the behavioral immobility response. Evidence has been accumulating indicating that epigenetic marks could be transgenerationally transmitted through the germline. Further research is needed to understand the molecular and epigenetic mechanisms underpinning this process.
|1.||Trollope, A.F; et al. Molecular and epigenetic mechanisms underlying cognitive and adaptive responses to stress. epigenomes.2017, 1(3).|
|2.||Zakhari, S. Alcohol metabolism and epigenetics changes. Alcohol Res.2013, 35(1):6-16.|