What is epigenetics?
Epigenetics is the study of moldable capacity of gene activity that gives information on gene function and provides a way to act directly upon them.
DNA methylation consists of the introduction of the methyl group in the 5 position of cytosine base in DNA.
This process is one of the most studied epigenetic mechanisms and it is essential for the correct development of organisms.
Aberrant DNA methylation is associated with loss of DNA homeostasis and genomic instability leading to the development of several diseases (e.g. cancer, neurological disorders, metabolic syndrome, etc.). Methylation usually occurs at CpG sites.
Interestingly, these sites are under-represented and
unequally distributed across the human genome, giving rise to vast low-density CpG regions with interspersed clusters located mainly on CpG islands. DNA methylation is catalyzed by DNA methyltransferases (DNMTs) that introduce the methyl group from a molecule of S-adenosylmethionine. DNMT1 is the enzyme primarily involved in the maintenance of methylation patterns with each cell replication. DNMT3a and DNMT3b have de novo methylating activity.
Histones are a family of basic proteins involved in the compaction of DNA in structural units called nucleosomes.
Each nucleosome is made of DNA wrapped around eight histone proteins called a histone octamer.
Each histone octamer is composed of two copies of the histone proteins H2A, H2B, H3, and H4. The nucleosome chain is then wrapped into a 30 nm spiral called a selenoid, where additional H1 histone (the linker histone) binds to the nucleosome to maintain the chromatin structure. Histones are chemically modified by different enzymes at external N- and C-terminal tails as well as at internal histone-fold domains. These post-translational modifications (PTMs) mainly consist of acetylation, methylation, phosphorylation, and carbonylation, and set the “histone code”.
Chemical modifications on histone tails change the expression pattern of some genes because PTMs have the potential to modify the structure of chromatin, thus activating or silencing genes.One of the most studied PTMs in histones is acetylation which is regulated by specific enzymes, like histone acetyltransferases (HATs) and histone deacetylases (HDACs) that modulate the balance of acetylated histones.
Alterations in the histone PTMs patterns are believed to deregulate the control of the chromatin-based process, ultimately leading to oncogenic transformation and the development of cancer. Consistent with this notion, aberrant patterns of histone PTMs have been found in a large number of human malignancies.
All core histone proteins have diverse variants that differ in a limited number of amino acids in their primary sequence.
These variants are involved in the indexing of the genome, in this way establishing different regulated regions that can be activated or repressed for transcription.
Hake and Allis established “the histone barcode” hypothesis (originally described for histone H3 variants), according to which genes are switched “on” or “off” according to PTMs, which can in turn be associated with the histone variant. As such, histone variants may confer a new level of gene expression regulation, they may be tissue or cell-specific or they may be related to a specific cellular event.
A recent study has shown that recurrent mutations in critical residues of the histone tail (K27M and G34R/G34V) in the replication-independent histone variant H3.3 are present in children and young adults with glioblastoma multiforme, a brain tumor that has a very poor prognosis. Thus, the analysis of mutations of histone and histone variants may be a useful tool for identifying several diseases and may unveil their pathogenesis since mutations in histones and their histone variants can change the functionality of these proteins. Specific mutations in conserved residues of histones are also associated with specific disease phenotypes.
The discovery of microRNAs (miRNAs) has revolutionized medical science because of their potential applications.
It has been calculated that the overall number of miRNAs in the human genome may be close to 1500, although new studies report ever higher numbers.
miRNAs are a class of small non-coding RNAs of 19–23 nucleotides that can negatively regulate gene expression as well as other epigenetic mechanisms, such as DNA methylation. It is estimated that as many as 30% of mammalian genes are regulated by miRNAs. miRNA signatures will be identified in several diseases over the coming years. One promising application of miRNAs will be the identification of a
specific miRNA profile that serves as a biomarker for disease diagnosis and prognosis. In addition, in the last five years evidence has shown the implication of miRNAs in the development of many cancers, by oncogene- or suppressor gene-related mechanisms.The relative stability of miRNAs in serum, plasma, urine, saliva, and other fluids make them suitable molecules for analysis in a clinical laboratory. Therefore, the study of miRNAs offers the opportunity to investigate whether specific miRNAs participate in metastatic pathways and will be useful for assessing the effectiveness of different therapies.