Key Points
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Many long non-coding RNAs (lncRNAs) are implicated in the regulation of gene expression. Dissection of several examples has yielded insights into three key mechanisms.
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LncRNAs can act as scaffolds to integrate the functions of diverse regulatory protein complexes.
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LncRNAs can localize to genomic DNA using proximity- and protein affinity-mediated interactions.
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LncRNAs can alter genome architecture and initiate the formation of nuclear compartments.
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The combination of these abilities enables lncRNAs to achieve unique regulatory functions, including spatial amplification of regulatory information, partitioning of the nucleus and dynamic assembly of nuclear compartments.
Abstract
Over the past decade, it has become clear that mammalian genomes encode thousands of long non-coding RNAs (lncRNAs), many of which are now implicated in diverse biological processes. Recent work studying the molecular mechanisms of several key examples — including Xist, which orchestrates X chromosome inactivation — has provided new insights into how lncRNAs can control cellular functions by acting in the nucleus. Here we discuss emerging mechanistic insights into how lncRNAs can regulate gene expression by coordinating regulatory proteins, localizing to target loci and shaping three-dimensional (3D) nuclear organization. We explore these principles to highlight biological challenges in gene regulation, in which lncRNAs are well-suited to perform roles that cannot be carried out by DNA elements or protein regulators alone, such as acting as spatial amplifiers of regulatory signals in the nucleus.
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Acknowledgements
We thank members of the Guttman laboratory, especially Sofia Quinodoz, for helpful discussions, and Sigrid Knemeyer for help with the figures. J.M.E. is supported by the Fannie and John Hertz Foundation and the Broad Institute. N.O. is supported by a postdoctoral fellowship from the California Institute of Technology. M.G. is a New York Stem Cell Foundation Robertson Investigator, an investigator at the Heritage Medical Research Institute, a Searle Scholar, a Pew-Steward scholar and an Alfred P. Sloan fellow. Research in the Guttman laboratory is funded by the National Institutes of Health (NIH) 4DN programme, an NIH Director's Early Independence Award, the New York Stem Cell Foundation, the Edward Mallinckrodt Foundation, Sontag Foundation, Searle Scholars Program, Pew-Steward Scholars programme and funds from the California Institute of Technology.
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Supplementary information S1 (table)
Summary of key long noncoding RNAs (lncRNAs) discussed in this Review (PDF 125 kb)
Glossary
- X chromosome inactivation
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(XCI). A process in early embryonic development whereby gene expression from one of the two X chromosomes in females is silenced to achieve balanced expression levels with X-linked genes in males.
- Polycomb group (PcG) proteins
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A protein family involved in modifying histones and modulating chromatin structure to silence gene expression. PcG proteins comprise two main complexes – Polycomb repressive complexes 1 and 2.
- Imprinted phase of XCI
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A process occurring on the paternally derived X chromosome of two- and four-cell stage embryos. Extra-embryonic tissues retain this imprinted pattern of XCI, whereas embryonic tissues reverse this imprinted pattern and then randomly inactivate one X chromosome.
- SR proteins
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Proteins that contain domains enriched in Arg–Ser dipeptides. Many SR proteins are nuclear and involved in RNA processing.
- Genomic imprinting
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An epigenetic phenomenon in which expression of a gene is restricted to a single allele based on parental origin.
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Engreitz, J., Ollikainen, N. & Guttman, M. Long non-coding RNAs: spatial amplifiers that control nuclear structure and gene expression. Nat Rev Mol Cell Biol 17, 756–770 (2016). https://doi.org/10.1038/nrm.2016.126
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DOI: https://doi.org/10.1038/nrm.2016.126
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