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Chromatin-associated RNAs as facilitators of functional genomic interactions

An Author Correction to this article was published on 04 July 2019

This article has been updated

Abstract

Mammalian genomes are extensively transcribed, which produces a large number of both coding and non-coding transcripts. Various RNAs are physically associated with chromatin, through being either retained in cis at their site of transcription or recruited in trans to other genomic regions. Driven by recent technological innovations for detecting chromatin-associated RNAs, diverse roles are being revealed for these RNAs and associated RNA-binding proteins (RBPs) in gene regulation and genome function. Such functions include locus-specific roles in gene activation and silencing, as well as emerging roles in higher-order genome organization, such as involvement in long-range enhancer–promoter interactions, transcription hubs, heterochromatin, nuclear bodies and phase transitions.

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Fig. 1: Different modes of RNA–chromatin interactions.
Fig. 2: Strategies for global analysis of RNA–chromatin interactions.
Fig. 3: Nascent-RNA-decorated transcription hubs and a model for RNA-nested hub formation.
Fig. 4: Roles of chromatin-associated nascent RNA in transcriptional activation or repression.
Fig. 5: RNA-dependent and RNA-independent feedback loops for establishing and locally spreading heterochromatin.
Fig. 6: RNAs in liquid–liquid phase separation and nuclear body formation.

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Change history

  • 04 July 2019

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

The authors are grateful for the critical comments of B. Hamilton and the referees, which helped to improve the manuscript. The work in the authors’ laboratories was supported by grants HG004659, GM049369 and GM052872 (to X.-D.F.) from the US National Institutes of Health.

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Nature Reviews Genetics thanks J. Lawrence, R. Jenner and A. Straight for their contribution to the peer review of this work.

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Correspondence to Xiang-Dong Fu.

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Glossary

Protein-coding mRNAs

RNAs that have protein-coding capacity after processing.

Non-coding RNAs

(ncRNAs). RNAs that do not have protein-coding capability, although some RNAs classified as ncRNAs actually encode small peptides.

Ribonucleoprotein particles

(RNPs). Particles consisting of RNAs and RNA-binding proteins.

3D genome

Genomic DNA organized in different functional states, forming higher-order structures in the 3D space of the nucleus.

RNA clouds

Traditionally referring to large-scale regions of accumulated RNA in microscopy images (particularly mammalian Xist RNA coating the entire inactive X chromosome), here we use a broader definition encompassing chromatin-associated RNA foci at various genomic scales, including RNAs associating with clusters of DNA elements or segments of chromosomes.

Promoters

DNA segments that nucleate the formation of the transcription initiation complex to drive transcription.

Enhancers

DNA segments that enhance transcription. Many active enhancers are now known to also generate RNA known as enhancer RNA.

Liquid–liquid phase separation

Formation of membrane-less assemblies or condensates of proteins or protein complexes that undergo active fusion and fission.

R-loop

An RNA:DNA hybrid with the non-template strand remaining as single-stranded DNA.

Heterochromatin

Compacted chromosomal regions that largely lack transcription activity.

Triplex

A three-strand RNA:DNA structure that involves non-canonical base-pairing between RNA and double-stranded DNA.

Shadow enhancer

A DNA element that is used as an alternative enhancer when another enhancer is inactivated.

Transcription hubs

Active gene clusters that may be far apart in terms of linear chromosomal distance but are folded into 3D spatial proximity. Genes in transcription hubs may functionally modulate one another, and their close spatial proximity allows local recycling of the transcription machinery.

Super-enhancers

DNA segments ranging in size from 10 to 40 kb that contain clusters of multiple active enhancer elements.

Typical enhancers

DNA segments, usually <0.5 kb in length, that can enhance transcription of nearby promoters.

Transcription factories

Nuclear regions that have relatively high concentrations of the transcription machinery.

Low-complexity domains

(LCDs). Protein domains containing dipeptide repeats enriched with glycine, tyrosine, serine, glutamine, phenylalanine, arginine and so forth.

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Li, X., Fu, XD. Chromatin-associated RNAs as facilitators of functional genomic interactions. Nat Rev Genet 20, 503–519 (2019). https://doi.org/10.1038/s41576-019-0135-1

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