Article series: Non-coding RNA

The rise of regulatory RNA

Journal name:
Nature Reviews Genetics
Volume:
15,
Pages:
423–437
Year published:
DOI:
doi:10.1038/nrg3722
Published online

Abstract

Discoveries over the past decade portend a paradigm shift in molecular biology. Evidence suggests that RNA is not only functional as a messenger between DNA and protein but also involved in the regulation of genome organization and gene expression, which is increasingly elaborate in complex organisms. Regulatory RNA seems to operate at many levels; in particular, it plays an important part in the epigenetic processes that control differentiation and development. These discoveries suggest a central role for RNA in human evolution and ontogeny. Here, we review the emergence of the previously unsuspected world of regulatory RNA from a historical perspective.

At a glance

Figures

  1. The rise of regulatory RNA
    Figure 1: The rise of regulatory RNA
  2. Complex expression of the genome and examples of non-coding RNA expression.
    Figure 2: Complex expression of the genome and examples of non-coding RNA expression.

    The mammalian transcriptional landscape is represented graphically with genes expressing ribosomal RNAs, tRNAs, small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), various protein-coding and non-coding genes (which encode mRNAs and long non-coding RNAs (lncRNAs), respectively), as well as genes expressing small regulatory RNAs such as microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs), promoter-associated short RNAs (PASRs), transcription initiation RNAs (tiRNAs) and splice site RNAs (spliRNAs), snoRNA-derived small RNAs and tRNA-derived small RNAs. The transcriptional units are not depicted to scale.

  3. Functional pathways of small regulatory RNAs.
    Figure 3: Functional pathways of small regulatory RNAs.

    MicroRNA (miRNA) precursors (that is, pri-miRNAs) are expressed as stem–loop structures75, which interact with Drosha76 and DGCR8 (also known as Pasha) (step 1). They are then processed into pre-miRNAs and exported from the nucleus by exportin 5 (step 2). These transcripts are further processed by Dicer to small (21–23-nucleotide) double-stranded RNAs, one strand of which is loaded into the Argonaute (AGO) component of the RNA-induced silencing complex (RISC) (step 3). Exogenously introduced small interfering RNAs (siRNAs) can also be processed by RISC. The endogenous miRNA or siRNA, or exogenously added siRNA, can then target the repression of translation (step 4) and/or cleavage of homology-containing transcripts81, 82 (step 5). Some small RNAs are functional in the nucleus. Exogenously introduced small antisense RNAs (asRNAs) can induce epigenetic silencing of targeted loci88, 342, 343 — a pathway that miRNAs may also use in the nucleus92 (step 6). Transcription initiation RNAs (tiRNAs) and splice site RNAs (spliRNAs)121, 122 are expressed through an unknown pathway that may involve RNA polymerase II (Pol II) backtracking and TFIIS cleavage123 (not shown); tiRNAs and spliRNAs are shown to modulate CCCTC-binding factor (CTCF) chromatin localization and to be associated with nucleosome positioning124 (step 7). DNMT3A, DNA (cytosine-5)-methyltransferase 3A; EZH2, enhancer of Zeste 2; H3K9ac, histone H3 lysine 9 acetylation; HDAC1, histone deacetylase 1; TARBP2, RISC-loading complex subunit TARBP2 (also known as TRBP).

  4. Various roles for long non-coding RNAs in cellular regulation.
    Figure 4: Various roles for long non-coding RNAs in cellular regulation.

    A | Long non-coding RNAs (lncRNAs) are expressed from many loci in the genome — sense and antisense, intronic, overlapping and intergenic with respect to nearby protein-coding loci — and function in both cis and trans. B | Nuclear functional lncRNAs can modulate gene expression both transcriptionally and epigenetically. Some lncRNAs interact with proteins to control the access of chromatin to cellular components and/or guide epigenetic regulatory complexes to target loci, which results in both transcriptional suppression201 (part Ba) and activation or suppression (that is, bimodal control)194 (part Bb). Proteins involved in chromatin modification — such as DNA (cytosine-5)-methyltransferase 3A (DNMT3A), enhancer of Zeste 2 (EZH2), euchromatic histone-lysine N-methyltransferase 2 (EHMT2; also known as G9a), chromodomain Y-like protein (CDYL), repressor element 1-silencing transcription factor (REST), co-repressor of REST (coREST), trithorax-activating complex MLL1 (Ref. 207) (not shown) and Polycomb repressive complex 2 (PRC2) — have been associated with lncRNA-mediated epigenetic silencing194, 201, 265; the histone demethylase LSD1 (also known as KDM1A) has been associated with activation of silent loci. Enhancer functional lncRNAs tether distal enhancer elements with their promoters344, 345, presumably in concert with a protein component that has yet to be determined (shown as 'unknown') (part Bc). Decoy functional lncRNAs affect transcription by binding to proteins such as DNMT1 to sequester them from their sites of action, which leads to a loss of maintenance of DNA methylation and gene activation263 (part Bd). C | Some lncRNAs can function in both nuclear and cytoplasmic compartments of the cell to affect gene expression and translation of mRNAs. Decoy functional lncRNA complexes affect microRNA (miRNA) targeting of mRNAs (part Ca). Some lncRNAs can interact with each other or with mRNAs to sequester small regulatory RNAs, such as miRNAs and therefore RNA-induced silencing complex (RISC), from protein-coding mRNAs201, 337, 338. Translational regulatory lncRNAs have been observed to recruit protein complexes that consist of heterogeneous nuclear ribonucloprotein K (hnRNPK), fragile X mental retardation syndrome-related protein 1 (FXR1), FXR2 and Poly(U)-binding splicing factor (PUF60) to homology-containing protein-coding mRNAs, where they bind to and sequester the mRNAs from the translational machinery346 and regulate translation (part Cb). lncRNAs can also bind to homology-containing mRNAs and recruit proteins such as QKI and serine/arginine-rich splicing factor 1 (SRSF1), both of which modulate the splicing of the targeted mRNA341 (part Cc). H3K9ac, histone H3 lysine 9 acetylation; me, methylation; Pol II, RNA polymerase II.

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Affiliations

  1. School of Biotechnology and Biomedical Sciences, University of New South Wales, Sydney, NSW 2052, Australia; and Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.

    • Kevin V. Morris
  2. Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia; the School of Biotechnology and Biomedical Sciences, and St. Vincent's Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.

    • John S. Mattick

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  • Kevin V. Morris

    Kevin V. Morris is an American born scientist. He trained at Humboldt State University, Arcata, California, USA, and the University of California at Davis and San Diego. He worked at the City of Hope National Medical Center, Duarte, California, and is currently an associate professor at the University of New South Wales, Sydney, Australia, and The Scripps Research Institute, La Jolla, California. His interests are to use non-coding RNA pathways to control gene expression and evolutionary states using various human disease model systems, such as cancer and HIV. Kevin V. Morris' homepage.

  • John S. Mattick

    John S. Mattick is the Executive Director of the Garvan Institute of Medical Research, Sydney, Australia, and Adjunct Professor at the University of New South Wales in Sydney. He was trained at the University of Sydney and Monash University in Melbourne, Australia. He has worked at Baylor College of Medicine in Houston, Texas, USA; the Commonwealth Scientific and Industrial Research Organisation (CSIRO) Division of Molecular Biology in Sydney; and the University of Queensland in Brisbane, Australia, where he was Foundation Director of the Institute for Molecular Bioscience and the Australian Genome Research Facility. His interests are in genomics, transcriptomics and RNA biology. John S. Mattick's homepage.

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