If we look upthe word epigenetic in the dictionary, the result will be: the process by whichthe expression of genetic information is modified on a molecular level withouta change to the DNA sequence. The word epigenetic was also defined by previousresearchers as “in addition to changes in genetic sequence”, “to act “on topof” or “in addition” to genetics” and “heritable changes in gene activity andexpression that occur without alteration in DNA sequence” 1-4.Various kinds of epigenetic processes have been discovered during the years,which include methylation, acetylation, phosphorylation, ubiquitylation andnon-coding RNA. Such alterations can be transmitted to daughter cells or, assuggested in recent experiments, can be reversed.
Epigenetic processes aresignificant to normal organism functions, however, if they develop incorrectly,severe unwanted health and mental effects could arise4. The mostfrequently studied epigenetic process is DNA methylation. It involves the covalentaddition or removal of a methyl group (CH3) to the fifth position of thecytosine base within CpG dinucleotides. This modification is catalyzed by DNAmethyltransferases (DNMTs), as DNMT1, DNMT3a and DNMT3b. DNMT3a and DNMT3b areconsidered de novo methyltransferases, initiating methylation to unmethylatedCpGs during embryonic development or in cancer cells5-7.
On the contrary, DNMT1 functions as the maintenance methyltransferase bymethylating hemimethylated CpGs after mitosis, hence transmitting themethylation patterns to daughter strands, along with contributing to thede novo methylation process 8; 9. Both classes aresaid to function co-operatively to methylate DNA usually in regions known asCpG islands where the occurrence of CpG dinucleotides is high. DNA methylationcauses gene silencing through two mechanisms; firstly, by decreasing theaffinity of transcription factors to gene promoters through steric hindranceand secondly by the direct binding of methyl CpG binding domain(MBD)-containing proteins to the methylated DNA, causing transcriptionrepression through chromatin condensation10. This gene silencing could bereversed by active DNA demethylation which mainly happens by the removal of themethyl group from 5-methylcytosine via Methyl-CpG binding domain proteins11. Anotherepigenetic regulation is histone modification which encounters any posttranslational modification regulating chromatin structure and function. Chromatinconsists of DNA and proteins bundled together in a compact way to fit insidethe nucleus4. These complexes can bemodified mainly through acetylation and methylation of the histone lysineresidues. The resultant effect differs according to the type of modificationand its location on the histone.
The lysine residues at the histone terminalsare subject to acetylation or deacetylation by histone acetyltransferases orhistone deacetylases. Acetylation decreases the positive charges of lysineresidues and reduces the affinity between histones and DNA which results indecondensation of the chromatin hence, disrupting the chromatin structure.Moreover, acetylated residues act as binding sites for histone modifyingenzymes or chromatin remodeling factors that facilitate gene expression12;13.
Histonemethylation occurs on various lysine residues with different degree ofmethylation thus giving a wide variety of results either repressive oractivating depending on the combination of factors14. Methylation of the lysine atthe fourth residue of histone H3 (H3K4Me) promotes a transcriptionally activeconformation, whereas H3K9Me promotes a transcriptionally repressiveconformation. H3K36Me can be activating or repressive, depending upon proximityto a gene promoter region15. Non-coding RNAs RNA species beyond mRNA which lack clear potential to encode proteinsor peptides, and they include intronic RNAs, microRNAs (miRNAs), circular RNAs(circRNAs), extracellular RNAs and long non-coding RNAs (lncRNAs), that will beour main focus in this review16.LncRNAs LncRNAs are adiverse group of transcripts whose natural functions and potential as drugtargets remain largely undefined. These RNA species are greater than 200nucleotides in length and do not encode protein.
lncRNAs are thought toencompass nearly 30,000 different transcripts in humans, hence lncRNAtranscripts account for the major part of the non-coding transcriptome. lncRNAdiscovery is still at a preliminary stage. LncRNAs biogenesis Some longnon-coding RNAs (lncRNAs) or classes of lncRNAs are regulated differentially atdifferent points of their biogenesis, maturation and degradation.
At thelevel of the chromatin state, lncRNAs and mRNAs exhibit similar properties,such as an enrichment of H3K4me3 at promoters; however, lncRNA genes have ahigher enrichment of H3K27ac and are more strongly repressed by certainchromatin remodelling complexes, such as Swr1, Isw2, Rsc and Ino80. Transcriptional initiation from divergent promoters differs for thesense (mRNA) and the antisense (lncRNA) directions; divergent antisensetranscription is enriched for H3K56ac and phosphorylation of RNA polymerase II(Pol II) Tyr1. Transcription in the divergent direction is further enhanced bythe SWI/SNF proteins and repressed by CAF-1. Transcriptional elongation is morestrongly regulated by DICER1 and MYC for lncRNAs than for mRNAs.
Theoccurrence of U1 and polyadenylation signals differs on either side ofbidirectional promoters (along the U1–PAS axis), favouring the splicing ofmRNAs in the sense direction and the cleavage and polyadenylation in thedivergent, antisense direction. Whereas mRNAs localize very specificallyto ribosomes in the cytoplasm, lncRNA localization is much more varied, as certainlncRNAs can occupy the chromatin, subnuclear domains, the nucleoplasm or thecytoplasm.