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  • br Epigenetics br Non coding RNA and aging Only of

    2019-07-05


    Epigenetics
    Non-coding RNA and aging Only 1.5–1.8% of the mammalian KRN 7000 price is transcribed to yield proteins. The rest is transcribed into noncoding RNAs (ncRNAs) that mostly include small (20–30 nt sncRNAs) and long (>200 nt lncRNAs) [318,319]. Noncoding RNAs represent a vast pool in the mammalian genome that may provide some of the missing links in the aging process [320]. SncRNAs are comprised mainly of inhibitory RNAs such as microRNAs (miRNAs), small inhibitory RNAs (siRNAs) and piwi-interesting RNAs (piRNAs) involved mainly in post-transcriptional gene regulation, mediated by mRNA degradation or disruption of translation. These have been studied in aging [[321], [322], [323], [324], [325]]. PCR arrays of serum samples from Baltimore Longitudinal Study of Aging subjects identified multiple differentially expressed miRNAs, including 6 miRNAs that correlated with subsequent longevity [326]. Five of these miRNAs targeted 24 aging-associated mRNAs which included PARP1, IGF1R and IGF2R mRNAs. LncRNAs are transcribed from the intergenic and intronic regions of the mammalian genome [319,327,328]. While the transcriptional regulatory sequences of lncRNAs are evolutionarily conserved, many lncRNAs are species- (including primate-) specific. Just as for mRNA, lncRNAs are transcribed by RNA polymerase II, then introns are removed, 5'methyl-capping takes place, and poly-adenylation occurs. They are characterized by well-defined transcriptional landmarks (histone H3-lysine 4 (H3K4) and H3K36 tri-methylation, H3K9 acetylation and CpG DNA methylation), and are regulated by common transcription factors such as p53, Oct and Nanog [[328], [329], [330]]. Based on their genomic location, orientation and mode of transcription, lncRNAs are arbitrarily classified further into sense, antisense, bi-directional, promoter-associated, enhancer-associated, pseudogene-associated, telomere-associated, circular and repeat-rich lncRNAs in a nonexclusive manner [319,327,331,332]. Most lncRNAs exhibit specific subcellular, cell, tissue and developmental expression patterns in mammals, which supports them having important biological functions KRN 7000 price such as development and differentiation, cell survival, cell proliferation and apoptosis, dosage compensation and gene imprinting, reprogramming of differentiated cells and maintenance of stem cells [320]. Most of the characterized lncRNAs are nuclear localized and act as enhancer RNAs (eRNAs), chromatin modifiers via recruitment of various DMTs, and histone modifiers via polycomb repressive complexes or histone methyltransferases [320]. Many lncRNAs affect key cellular processes such as proliferation, differentiation, quiescence, senescence, stress and immune response, and many other cellular functions related to aging [333]. A list of lncRNAs involved in regulation of cellular senescence and aging has been compiled [320]. Some are antisense transcripts complementary to mRNA transcripts of the same gene [320]. Among these are lncRNAs differentially expressed in senescent cells [334] and that suppress mRNA expression [320]. Other lncRNAs are encoded by pseudogenes and act to negatively regulate the expression levels of the corresponding mRNA for cell adhesion molecules and translation machinery components in senescent cells. These effects could affect cell morphology, growth and division, as well as expression of various senescence-associated proteins, so contributing to cellular senescence and aging [320]. Yet other lncRNAs are encoded in intergenic DNA and affect a multitude of different intracellular processes, some of which may contribute to senescence and aging [320]. A class of heterogeneous 5′-UUAGGG-3′ repeat-containing lncRNAs – telomere repeat containing RNA (TERRA) – is partly associated with telomeric heterochromatin [[335], [336], [337]]. When strongly upregulated, TERRA can promote telomere dysfunction such as shortening, decreased stability and heterochromatin formation [320].