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WIREs Dev Biol
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The role of noncoding RNAs in chromatin regulation during differentiation

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Abstract A myriad of nuclear noncoding RNAs (ncRNAs) have been discovered since the paradigm of RNAs as plain conveyors of protein translation was discarded. There is increasing evidence that at vital intersections of developmental pathways, ncRNAs target the chromatin modulating machinery to its site of action. However, the mechanistic details of processes involved are still largely unclear, and well‐characterized metazoan ncRNA species implicated in chromatin regulation during differentiation remain few. Nevertheless, four major categories are slowly emerging: cis‐acting antisense ncRNAs that flag the neighboring genes for the propagation of chromatin marks; allele‐specific ncRNAs that perform similar tasks, but target larger loci that typically vary in size from hundreds of thousands of base pairs to a whole chromosome; structural ncRNAs proposed to act as scaffolds that couple chromatin shaping complexes of distinct functionalities; and cofactor ncRNAs with a capacity to inhibit or activate essential components of the intertwined chromatin and transcription apparatuses. WIREs Dev Biol 2012. doi: 10.1002/wdev.41 For further resources related to this article, please visit the WIREs website.

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Pausing of polymerase II, a hallmark feature at bivalent promoters of key developmental factors, is intimately affected by two noncoding RNAs: U1 and 7SK. (a) The kinase subunit of TFIIH complex, CDK7, catalyzes the phosphorylation of serine 5, a modification favorable to transcription initiation but not sufficient for its elongation, at the RNA polymerase II (RNAPII) C‐terminal repeat in a U1 snRNA dependent manner. CDK7 also mediates the phosphorylation of serine 7, which is poorly understood but necessary for the transcription of snRNAs including U1.52 (b) Crucial differentiation‐related genes are poised for activation by paused polymerases typically accompanied by NELF (negative elongation factor) and DSIF (DRB sensitivity‐inducing factor), all three of which are putative targets of the positive transcription elongation factor P‐TEFb (CDK9/Cyclin T1). The 7SK snRNA introduces an allosteric change in the HEXIM1 protein, converting it to an inhibitor of P‐TEFb. (c) When bound by BRD4, a factor antagonistic and mutually exclusive to HEXIM1/7SK, the kinase functionality of P‐TEFb is enhanced. This contributes to the dissociation of NELF, conversion of DSIF from a negative to a positive elongation factor, and a RNAPII modification requisite for elongation: phosphorylation of serine 2.

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Many developmentally crucial imprinted mammalian small RNAs are genomically embedded in, and post‐transcriptionally derived from, the introns of long noncoding host genes. Examples of such small RNAs include the primate homologs of the vertebrate‐wide embryogenesis regulator miR‐430/427/302 at the human chromosome 19 miRNA cluster (C19MC) as well as the SNORD116 small nucleolar RNAs (snoRNAs) implicated in the etiology of the Prader‐Willi syndrome. Hundreds of miRNA and snoRNA genes, many of which are currently not well understood, inhabit these and other similar imprinted loci. The host ncRNAs localize near their transcription site in a coordinated and allele‐specific manner, and future research may show that they contribute to the establishment and maintenance of chromatin markers in cis. The schematic diagrams are not drawn to scale.

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Major modes of action for noncoding RNAs implicated in the modulation of metazoan chromatin during differentiation‐related processes. (a) Dosage compensation and imprinting ncRNAs, for example, Xist and Kcnq1ot1 (pictured), facilitate chromosome‐ or locus‐wide recognition of the silenced allele. (b) Cis‐acting transcripts such as ANRIL, Evf2, and HOTTIP are derived from the opposite strand of the locus they target for PcG‐ or TrxG‐mediated chromatin regulation. (c) HOTAIR, and putatively other currently uncharacterized ncRNAs, operate as structural scaffolds by bridging chromatin complexes with synergic enzymatic functionalities. (d) Two abundant small nuclear RNAs, 7SK, and U1, function as cofactors of key chromatin components; here, a novel proposed inhibitory effect of 7SK on HMGA1 is visualized.

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