Diverse roles of regulatory non-coding RNAs

Diverse roles of regulatory non-coding RNAs A large fraction of mammalian genome can be transcribed to produce various RNAs, of which only a small subset can serve as the template for protein translation. The RNAs that do not code for proteins are collectively referred as non-coding RNA, which can serve as key functional components or regulatory molecules of gene expression. The best understood regulatory non-coding RNAs include microRNAs (miRNAs) that control degradation and/or translation of mRNAs and long non-coding RNAs (lncRNAs) that often control chromatin structure and gene transcription. Depending on the specific targets regulated by non-coding RNAs, the biological roles of the regulatory non-coding RNA can be very diverse. In the past decade, novel functions of many non-coding RNAs have been discovered that control important biological processes such as cell differentiation; however, current work may only present a tip of iceberg of all possible functions of non-coding RNAs. In this issue, one review and four research papers provide new insights into the biological roles of regulatory non-coding RNA. Drs Kyle Biggar and Kenneth Storey contributed a comprehensive review on how the microRNA-mediated gene regulation helps animals to survive the extreme stress conditions, including the hibernation, freeze tolerance, and anoxia tolerance. The cells under extreme stress condition must halt its production of proteins and biosynthesis of RNA, which has to be achieved through molecular mechanisms that are inducible and reversible. Recent studies have suggested that microRNA may have a major regulatory influence over a number of cellular processes essential to prolonged environmental stress survival. The authors have given a detailed summary on recent studies that have highlighted the role of stress-responsive microRNA in the regulation of various metabolically depressed states. Collectively, these studies indicate a conserved principle of microRNA stress response across phylogeny, and this review summarizes research advances and provides insightful perspectives on the roles of microRNA in facilitating stress survival. An important function of lncRNAs is to regulate transcription of specific genes in nucleus, which is often mediated through the specific interactions between lncRNAs and certain RNA-binding proteins (RBPs). Dr Shizuka Uchida and his colleagues identified a novel muscle-enriched lncRNA, Myolinc (AK142388), which promotes myogenesis by inducing the expression of muscle-specific genes including Filip1. They found that Myolinc is predominately localized in the nucleus, and its levels increase upon myogenic differentiation. Myolinc binds to a DNA/RNA-binding protein TDP-43, which recruits the TDP-43 to the promoters of many muscle genes (e.g. Filip1, Acta1, and MyoD) to enhance the expression of their targets. Consistently, knockdown of Myolinc or TDP-43 can inhibit myogenic differentiation in cultured cells or skeletal muscle regeneration in adult mice. Altogether, this study identifies a novel lncRNA that controls key regulatory networks of myogenesis. In addition to promoting target gene expression, lncRNAs can often silence the expression of their targets by binding to different RBP partners. Dr Jiuhong Kang’s group reported a non-coding RNA (linc1614) that interacts with polycomb repressive complex 2 (PRC2) to repress developmental genes, thus playing a key role in acquisition and maintenance of pluripotency. Mechanistically, linc1614 serves as a specific partner of the core factor Sox2 in the repression of many developmental genes to maintain pluripotency. This work exemplifies a common mechanism by which lncRNAs serve as a key component of the polycomb repressive complex to silence gene transcription through epigenetic regulation. In this regulatory paradigm, lncRNAs may function as a scaffold of the silencing complex or provide the specificity of gene silencing. The biological functions of non-coding RNAs are often affected by their associated RBP partners and their cellular locations; however, the localization diversity of non-coding RNAs and their target proteins has not been systematically studied. In this issue, Drs Lixin Cheng and Kwong-Sak Leung reported a new algorithm (ncTALENT) to quantify the target localization diversity of non-coding RNAs using the public datasets of non-coding RNA–protein interaction and protein subcellular localization. This method can be used to estimate the target localization of non-coding RNAs, providing new information on the diverse subcellular locations and potential functions of lncRNAs under various conditions. Moreover, the authors found that lncRNAs in multiple cancers are prone to have high target localization diversity. The analysis of gastric cancer further suggests that the target localization diversity of lncRNAs is an important feature closely related to clinical prognosis. Since accumulating evidences have suggested that many lncRNAs play important roles in cell differentiation and animal development, it is tempting to assume that most lncRNAs have essential roles in the normal life of animals. However, a recent collaboration between Drs Xiaohua Shen and Naihe Jing’s groups reported a rather surprising finding that knockout of many conserved and highly expressed lncRNAs does not lead to obvious phenotype in mouse models. Among the 12 lncRNAs that were systematically knocked out in mice, only one lncRNA (Hand2as) knockout caused a perinatal lethal phenotype. This finding suggests that most lncRNAs may serve as modulators (instead of master regulators) to fine-tune the spatiotemporal expression of pleiotropic developmental loci, which provide certain regulatory plasticity. Therefore, ‘comprehensive and careful revelation of the in vivo functions of lncRNAs in animal models remains the main challenge for the lncRNA field’. © The Author(s) (2018). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Molecular Cell Biology Oxford University Press

Diverse roles of regulatory non-coding RNAs

Journal of Molecular Cell Biology , Volume Advance Article (2) – May 11, 2018

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Publisher
Oxford University Press
Copyright
© The Author(s) (2018). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.
ISSN
1674-2788
eISSN
1759-4685
D.O.I.
10.1093/jmcb/mjy026
Publisher site
See Article on Publisher Site

Abstract

A large fraction of mammalian genome can be transcribed to produce various RNAs, of which only a small subset can serve as the template for protein translation. The RNAs that do not code for proteins are collectively referred as non-coding RNA, which can serve as key functional components or regulatory molecules of gene expression. The best understood regulatory non-coding RNAs include microRNAs (miRNAs) that control degradation and/or translation of mRNAs and long non-coding RNAs (lncRNAs) that often control chromatin structure and gene transcription. Depending on the specific targets regulated by non-coding RNAs, the biological roles of the regulatory non-coding RNA can be very diverse. In the past decade, novel functions of many non-coding RNAs have been discovered that control important biological processes such as cell differentiation; however, current work may only present a tip of iceberg of all possible functions of non-coding RNAs. In this issue, one review and four research papers provide new insights into the biological roles of regulatory non-coding RNA. Drs Kyle Biggar and Kenneth Storey contributed a comprehensive review on how the microRNA-mediated gene regulation helps animals to survive the extreme stress conditions, including the hibernation, freeze tolerance, and anoxia tolerance. The cells under extreme stress condition must halt its production of proteins and biosynthesis of RNA, which has to be achieved through molecular mechanisms that are inducible and reversible. Recent studies have suggested that microRNA may have a major regulatory influence over a number of cellular processes essential to prolonged environmental stress survival. The authors have given a detailed summary on recent studies that have highlighted the role of stress-responsive microRNA in the regulation of various metabolically depressed states. Collectively, these studies indicate a conserved principle of microRNA stress response across phylogeny, and this review summarizes research advances and provides insightful perspectives on the roles of microRNA in facilitating stress survival. An important function of lncRNAs is to regulate transcription of specific genes in nucleus, which is often mediated through the specific interactions between lncRNAs and certain RNA-binding proteins (RBPs). Dr Shizuka Uchida and his colleagues identified a novel muscle-enriched lncRNA, Myolinc (AK142388), which promotes myogenesis by inducing the expression of muscle-specific genes including Filip1. They found that Myolinc is predominately localized in the nucleus, and its levels increase upon myogenic differentiation. Myolinc binds to a DNA/RNA-binding protein TDP-43, which recruits the TDP-43 to the promoters of many muscle genes (e.g. Filip1, Acta1, and MyoD) to enhance the expression of their targets. Consistently, knockdown of Myolinc or TDP-43 can inhibit myogenic differentiation in cultured cells or skeletal muscle regeneration in adult mice. Altogether, this study identifies a novel lncRNA that controls key regulatory networks of myogenesis. In addition to promoting target gene expression, lncRNAs can often silence the expression of their targets by binding to different RBP partners. Dr Jiuhong Kang’s group reported a non-coding RNA (linc1614) that interacts with polycomb repressive complex 2 (PRC2) to repress developmental genes, thus playing a key role in acquisition and maintenance of pluripotency. Mechanistically, linc1614 serves as a specific partner of the core factor Sox2 in the repression of many developmental genes to maintain pluripotency. This work exemplifies a common mechanism by which lncRNAs serve as a key component of the polycomb repressive complex to silence gene transcription through epigenetic regulation. In this regulatory paradigm, lncRNAs may function as a scaffold of the silencing complex or provide the specificity of gene silencing. The biological functions of non-coding RNAs are often affected by their associated RBP partners and their cellular locations; however, the localization diversity of non-coding RNAs and their target proteins has not been systematically studied. In this issue, Drs Lixin Cheng and Kwong-Sak Leung reported a new algorithm (ncTALENT) to quantify the target localization diversity of non-coding RNAs using the public datasets of non-coding RNA–protein interaction and protein subcellular localization. This method can be used to estimate the target localization of non-coding RNAs, providing new information on the diverse subcellular locations and potential functions of lncRNAs under various conditions. Moreover, the authors found that lncRNAs in multiple cancers are prone to have high target localization diversity. The analysis of gastric cancer further suggests that the target localization diversity of lncRNAs is an important feature closely related to clinical prognosis. Since accumulating evidences have suggested that many lncRNAs play important roles in cell differentiation and animal development, it is tempting to assume that most lncRNAs have essential roles in the normal life of animals. However, a recent collaboration between Drs Xiaohua Shen and Naihe Jing’s groups reported a rather surprising finding that knockout of many conserved and highly expressed lncRNAs does not lead to obvious phenotype in mouse models. Among the 12 lncRNAs that were systematically knocked out in mice, only one lncRNA (Hand2as) knockout caused a perinatal lethal phenotype. This finding suggests that most lncRNAs may serve as modulators (instead of master regulators) to fine-tune the spatiotemporal expression of pleiotropic developmental loci, which provide certain regulatory plasticity. Therefore, ‘comprehensive and careful revelation of the in vivo functions of lncRNAs in animal models remains the main challenge for the lncRNA field’. © The Author(s) (2018). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Journal of Molecular Cell BiologyOxford University Press

Published: May 11, 2018

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