Epigenomics

Epigenomics is the study of the complete set of epigenetic modifications on the genetic material of a cell, known as the epigenome. The field is analogous to genomics and proteomics, which are the study of the genome and proteome of a cell. Epigenetic modifications are reversible modifications on a cell's DNA or histones that affect gene expression without altering the DNA sequence. Epigenomic maintenance is a continuous process and plays an important role in stability of eukaryotic genomes by taking part in crucial biological mechanisms like DNA repair. Plant flavones are said to be inhibiting epigenomic marks that cause cancers. Two of the most characterized epigenetic modifications are DNA methylation and histone modification. Epigenetic modifications play an important role in gene expression and regulation, and are involved in numerous cellular processes such as in differentiation/development and tumorigenesis. The study of epigenetics on a global level has been made possible only recently through the adaptation of genomic high-throughput assays. Epigenomics is the study of the complete set of epigenetic modifications on the genetic material of a cell, known as the epigenome. The field is analogous to genomics and proteomics, which are the study of the genome and proteome of a cell. Epigenetic modifications are reversible modifications on a cell's DNA or histones that affect gene expression without altering the DNA sequence. Epigenomic maintenance is a continuous process and plays an important role in stability of eukaryotic genomes by taking part in crucial biological mechanisms like DNA repair. Plant flavones are said to be inhibiting epigenomic marks that cause cancers. Two of the most characterized epigenetic modifications are DNA methylation and histone modification. Epigenetic modifications play an important role in gene expression and regulation, and are involved in numerous cellular processes such as in differentiation/development and tumorigenesis. The study of epigenetics on a global level has been made possible only recently through the adaptation of genomic high-throughput assays. The mechanisms governing phenotypic plasticity, or the capacity of a cell to change its state in response to stimuli, have long been the subject of research (Phenotypic plasticity 1). The traditional central dogma of biology states that the DNA of a cell is transcribed to RNA, which is translated to proteins, which perform cellular processes and functions. A paradox exists, however, in that cells exhibit diverse responses to varying stimuli and that cells sharing identical sets of DNA such as in multicellular organisms can have a variety of distinct functions and phenotypes. Classical views have attributed phenotypic variation to differences in primary DNA structure, be it through aberrant mutation or an inherited sequence allele. However, while this did explain some aspects of variation, it does not explain how tightly coordinated and regulated cellular responses, such as differentiation, are carried out. A more likely source of cellular plasticity is through the Regulation of gene expression, such that while two cells may have near identical DNA, the differential expression of certain genes results in variation. Research has shown that cells are capable of regulating gene expression at several stages: mRNA transcription, processing and transportation as well as in protein translation, post-translational processing and degradation. Regulatory proteins that bind to DNA, RNA, and/or proteins are key effectors in these processes and function by positively or negatively regulating specific protein level and function in a cell. And, while DNA binding transcription factors provide a mechanism for specific control of cellular responses, a model where DNA binding transcription factors are the sole regulators of gene activity is also unlikely. For example, in a study of Somatic-cell nuclear transfer, it was demonstrated that stable features of differentiation remain after the nucleus is transferred to a new cellular environment, suggesting that a stable and heritable mechanism of gene regulation was involved in the maintenance of the differentiated state in the absence of the DNA binding transcription factors. With the finding that DNA methylation and histone modifications are stable, heritable, and also reversible processes that influence gene expression without altering DNA primary structure, a mechanism for the observed variability in cell gene expression was provided. These modifications were termed epigenetic, from epi “on top of” the genetic material “DNA” (Epigenetics 1). The mechanisms governing epigenetic modifications are complex, but through the advent of high-throughput sequencing technology they are now becoming better understood. Genomic modifications that alter gene expression that cannot be attributed to modification of the primary DNA sequence and that are heritable mitotically and meiotically are classified as epigenetic modifications. DNA methylation and histone modification are among the best characterized epigenetic processes. The first epigenetic modification to be characterized in depth was DNA methylation. As its name implies, DNA methylation is the process by which a methyl group is added to DNA. The enzymes responsible for catalyzing this reaction are the DNA methyltransferases (DNMTs). While DNA methylation is stable and heritable, it can be reversed by an antagonistic group of enzymes known as DNA de-methylases. In eukaryotes, methylation is most commonly found on the carbon 5 position of cytosine residues (5mC) adjacent to guanine, termed CpG dinucleotides. DNA methylation patterns vary greatly between species and even within the same organism. The usage of methylation among animals is quite different; with vertebrates exhibiting the highest levels of 5mC and invertebrates more moderate levels of 5mC. Some organisms like Caenorhabditis elegans have not been demonstrated to have 5mC nor a conventional DNA methyltransferase; this would suggest that other mechanisms other than DNA methylation are also involved. Within an organism, DNA methylation levels can also vary throughout development and by region. For example, in mouse primordial germ cells, a genome wide de-methylation even occurs; by implantation stage, methylation levels return to their prior somatic levels. When DNA methylation occurs at promoter regions, the sites of transcription initiation, it has the effect of repressing gene expression. This is in contrast to unmethylated promoter regions which are associated with actively expressed genes. The mechanism by which DNA methylation represses gene expression is a multi-step process. The distinction between methylated and unmethylated cytosine residues is carried out by specific DNA-binding proteins. Binding of these proteins recruit histone deacetylases (HDACs) enzyme which initiate chromatin remodeling such that the DNA becoming less accessible to transcriptional machinery, such as RNA polymerase, effectively repressing gene expression.