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Regulation of gene expression by cis-acting long non-coding RNAs

Abstract

Long non-coding RNAs (lncRNAs) are diverse transcription products emanating from thousands of loci in mammalian genomes. Cis-acting lncRNAs, which constitute a substantial fraction of lncRNAs with an attributed function, regulate gene expression in a manner dependent on the location of their own sites of transcription, at varying distances from their targets in the linear genome. Through various mechanisms, cis-acting lncRNAs have been demonstrated to activate, repress or otherwise modulate the expression of target genes. We discuss the activities that have been ascribed to cis-acting lncRNAs, the evidence and hypotheses regarding their modes of action, and the methodological advances that enable their identification and characterization. The emerging principles highlight lncRNAs as transcriptional units highly adept at contributing to gene regulatory networks and to the generation of fine-tuned spatial and temporal gene expression programmes.

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Fig. 1: Genomic locations and prevalence of cis-acting long non-coding RNAs.
Fig. 2: Mechanisms of action of activating cis-acting long non-coding RNAs.
Fig. 3: Functions of repressive cis-acting long non-coding RNAs.
Fig. 4: Plausible functions of cis-acting long non-coding RNAs.
Fig. 5: Methods for mapping functional features in cis-acting long non-coding RNAs.

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Acknowledgements

The authors would like to thank A. Shkumatava, S. Nakagawa, L. Chen, C. Ross, H. Hezroni, M. Goldrich and members of the Ulitsky laboratory for helpful discussions and comments on the manuscript.

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Glossary

Enhancers

DNA regulatory elements that activate gene transcription. Enhancers can operate from nearby or within their targets, or across large genomic distances.

Transcription factors

(TFs). Proteins that bind to specific DNA sequence motifs found within regulatory DNA elements — either promoters or enhancers — to modulate gene expression.

Chromatin remodellers

Proteins that regulate gene expression by altering chromatin structure. Two main groups exist: those that mediate post-translational modifications of histones; and ATP-dependent chromatin remodellers, which regulate the association with and location of nucleosomes along the DNA.

Super-enhancer

A particularly active and cell type-specific enhancer. Demarcated by high levels of chromatin modifications such as histone 3 lysine 27 acetylation (H3K27ac) and long sequence stretches bound by transcription factors and coactivators such as Mediator.

Topologically associating domain

(TAD). A genomic region with an average size of ~1 Mb characterized by high-density chromatin interactions. Sequences within TADs tend to form interactions with one another but less so with sequences in other TADs.

Enhancer RNAs

(eRNAs). A species of bidirectional, unstable non-coding RNAs produced at enhancers. Considered a hallmark of active enhancers and sometimes used for enhancer annotation.

CTCF

A transcription factor that acts primarily in chromatin 3D architecture regulation, through anchoring long-range chromatin loops and demarcating topologically associating domain boundaries.

Polycomb repressive complex 2

(PRC2). A histone methyltransferase protein complex that induces trimethylation of histone 3 lysine 27 (H3K27), a histone modification associated with long-term epigenetic silencing.

Vernalization

The process of induction of plant flowering, brought on by exposure to prolonged cold temperatures.

Enhancer competition

Two (or more) transcriptional units that can be activated by the same enhancer, and which compete over direct binding to and activation by that enhancer.

Transcriptional interference

A process whereby transcription through one genomic region interferes with transcription of a nearby (often overlapping) locus, for example, by curbing the recruitment of trans factors such as transcription factors or chromatin remodellers, or through deposition of chromatin modifications incompatible with transcription initiation.

Auto-regulatory feedback loops

A type of transcriptional regulation network in which a gene product regulates its own levels, for example, a transcription factor which binds its own locus and activates (or represses) transcription.

Disordered regions

Proteins or regions within proteins that do not adopt an ordered or well-defined 3D structure. These regions can serve as linkers between structured regions, or be functional themselves.

CRISPR–Cas9

A bacterial immune mechanism whereby a Cas9 protein uses short guide RNA (gRNA) sequences to target and cleave foreign DNA. CRISPR–Cas9 can be used for gene editing, by ectopic expression of both Cas9 and a gRNA that targets the gene of interest.

CRISPR display

Utilization of CRISPR–Cas9 for the recruitment of non-protein components. For example, long non-coding RNA sequences can be fused to the guide RNA and be brought to the target locus via ‘dead’ Cas9.

Self-cleaving ribozyme sequences

RNA sequences that can catalyse a reaction that would cut their own RNA.

RNA interference

(RNAi). Short non-coding RNA molecules — either microRNAs or short interfering RNAs — bind to complementary sequences in the target genes, leading to translation inhibition or target RNA degradation.

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Gil, N., Ulitsky, I. Regulation of gene expression by cis-acting long non-coding RNAs. Nat Rev Genet 21, 102–117 (2020). https://doi.org/10.1038/s41576-019-0184-5

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