If the DNA sequence. The word epigenetic was also

If we look up
the word epigenetic in the dictionary, the result will be: the process by which
the expression of genetic information is modified on a molecular level without
a change to the DNA sequence. The word epigenetic was also defined by previous
researchers as “in addition to changes in genetic sequence”, “to act “on top
of” or “in addition” to genetics” and “heritable changes in gene activity and
expression 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 and
non-coding RNA. Such alterations can be transmitted to daughter cells or, as
suggested in recent experiments, can be reversed. Epigenetic processes are
significant to normal organism functions, however, if they develop incorrectly,
severe unwanted health and mental effects could arise4.

 

The most
frequently studied epigenetic process is DNA methylation. It involves the covalent
addition or removal of a methyl group (CH3) to the fifth position of the
cytosine base within CpG dinucleotides. This modification is catalyzed by DNA
methyltransferases (DNMTs), as DNMT1, DNMT3a and DNMT3b. DNMT3a and DNMT3b are
considered de novo methyltransferases, initiating methylation to unmethylated
CpGs during embryonic development or in cancer cells5-7.
On the contrary, DNMT1 functions as the maintenance methyltransferase by
methylating hemimethylated CpGs after mitosis, hence transmitting the
methylation patterns to daughter strands, along with contributing to the
de novo methylation process 8; 9. Both classes are
said to function co-operatively to methylate DNA usually in regions known as
CpG islands where the occurrence of CpG dinucleotides is high. DNA methylation
causes gene silencing through two mechanisms; firstly, by decreasing the
affinity of transcription factors to gene promoters through steric hindrance
and secondly by the direct binding of methyl CpG binding domain
(MBD)-containing proteins to the methylated DNA, causing transcription
repression through chromatin condensation10. This gene silencing could be
reversed by active DNA demethylation which mainly happens by the removal of the
methyl group from 5-methylcytosine via Methyl-CpG binding domain proteins11.

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Another
epigenetic regulation is histone modification which encounters any post
translational modification regulating chromatin structure and function. Chromatin
consists of DNA and proteins bundled together in a compact way to fit inside
the nucleus4. These complexes can be
modified mainly through acetylation and methylation of the histone lysine
residues. The resultant effect differs according to the type of modification
and its location on the histone. The lysine residues at the histone terminals
are subject to acetylation or deacetylation by histone acetyltransferases or
histone deacetylases. Acetylation decreases the positive charges of lysine
residues and reduces the affinity between histones and DNA which results in
decondensation of the chromatin hence, disrupting the chromatin structure.
Moreover, acetylated residues act as binding sites for histone modifying
enzymes or chromatin remodeling factors that facilitate gene expression12;
13. Histone
methylation occurs on various lysine residues with different degree of
methylation thus giving a wide variety of results either repressive or
activating depending on the combination of factors14. Methylation of the lysine at
the fourth residue of histone H3 (H3K4Me) promotes a transcriptionally active
conformation, whereas H3K9Me promotes a transcriptionally repressive
conformation. H3K36Me can be activating or repressive, depending upon proximity
to a gene promoter region15.

 

Non-coding RNAs

 

RNA species beyond mRNA which lack clear potential to encode proteins
or peptides, and they include intronic RNAs, microRNAs (miRNAs), circular RNAs
(circRNAs), extracellular RNAs and long non-coding RNAs (lncRNAs), that will be
our main focus in this review16.

LncRNAs

 

LncRNAs are a
diverse group of transcripts whose natural functions and potential as drug
targets remain largely undefined. These RNA species are greater than 200
nucleotides in length and do not encode protein. lncRNAs are thought to
encompass nearly 30,000 different transcripts in humans, hence lncRNA
transcripts account for the major part of the non-coding transcriptome. lncRNA
discovery is still at a preliminary stage.

 

LncRNAs biogenesis

 

Some long
non-coding RNAs (lncRNAs) or classes of lncRNAs are regulated differentially at
different points of their biogenesis, maturation and degradation. At the
level of the chromatin state, lncRNAs and mRNAs exhibit similar properties,
such as an enrichment of H3K4me3 at promoters; however, lncRNA genes have a
higher enrichment of H3K27ac and are more strongly repressed by certain
chromatin remodelling complexes, such as Swr1, Isw2, Rsc and Ino80. 

Transcriptional initiation from divergent promoters differs for the
sense (mRNA) and the antisense (lncRNA) directions; divergent antisense
transcription is enriched for H3K56ac and phosphorylation of RNA polymerase II
(Pol II) Tyr1. Transcription in the divergent direction is further enhanced by
the SWI/SNF proteins and repressed by CAF-1. Transcriptional elongation is more
strongly regulated by DICER1 and MYC for lncRNAs than for mRNAs. The
occurrence of U1 and polyadenylation signals differs on either side of
bidirectional promoters (along the U1–PAS axis), favouring the splicing of
mRNAs in the sense direction and the cleavage and polyadenylation in the
divergent, antisense direction. Whereas mRNAs localize very specifically
to ribosomes in the cytoplasm, lncRNA localization is much more varied, as certain
lncRNAs can occupy the chromatin, subnuclear domains, the nucleoplasm or the
cytoplasm.