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Molecular Biology of Long Non-Coding Rnas Molecular Biology of Long Non-Coding Rnas Ahmad M Ahmad M. Khalil · Jeff Coller Editors Molecular Biology of Long Non-coding RNAs Molecular Biology of Long Non-coding RNAs Ahmad M. Khalil • Jeff Coller Editors Molecular Biology of Long Non-coding RNAs 123 Editors Ahmad M. Khalil Jeff Coller School of Medicine Case Western Reserve University Cleveland, OH USA ISBN 978-1-4614-8620-6 ISBN 978-1-4614-8621-3 (eBook) DOI 10.1007/978-1-4614-8621-3 Springer New York Heidelberg Dordrecht London Library of Congress Control Number: 2013948744 Ó Springer Science+Business Media New York 2013 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher’s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) Preface The mammalian genome encodes both coding and non-coding transcripts that work synergistically to build and organize cellular structures, and regulate gene expression patterns, which ultimately determine cell identity and function. While coding transcripts serve mostly as templates for protein synthesis, non-coding RNA transcripts, which by definition lack significant protein-coding capacity, participate in a wide range of cellular functions. These functions include organi- zation of protein synthesis (e.g., ribosomal RNAs and transfer RNAs), regulation of protein synthesis (e.g., micro RNAs), and regulation of gene expression at the transcriptional and post-transcriptional level (e.g., long non-coding RNAs). This book will focus on the recently discovered and less understood class of long non-coding RNAs (lncRNAs). This class of non-coding RNAs has only been recently characterized on a genome-wide scale, and only a small fraction of total transcripts is functionally characterized to date. lncRNAs are generally defined as RNA polymerase II transcripts that are longer than 200 nucleotides but lack sig- nificant protein-coding capacity. lncRNAs are capped, spliced, and poly- adenylated; however, a large fraction of lncRNAs are retained in the nucleus. Both experimental and bioinformatics analyses of the promoters of lncRNAs indicate that they are regulated by the same transcription factors as protein-coding genes. Also, many lncRNAs share a similar chromatin signature to protein-coding genes, suggesting that the transcription of lncRNAs follows the same rules as protein- coding genes. Although only a small fraction of lncRNAs has been functionally character- ized, the functions and mechanisms of lncRNAs appear to be diverse. Some lncRNAs (e.g., Xist and Tsix) are involved in the regulation of X chromosome inactivation (Xi) in mammalian females. For example, the lncRNA Xist (X inactive specific transcript) is required for the initiation and maintenance of Xi, which results in the inactivation of *80 % of protein-coding genes on the inactive X chromosome. While Xist regulate gene expression on the X chro- mosome, other lncRNAs also regulate gene expression but throughout the gen- ome. For example, the lncRNA HOTAIR, which is transcribed from the HOX-C locus, regulate gene expression not of nearby genes, but of genes in the HOX-D cluster and other genes scattered throughout the genome. Xist and HOTAIR are two examples of a number of lncRNAs that have been studied to date that regulate gene expression by guiding and recruiting chromatin modifying v vi Preface complexes to the genome either in cis or in trans. Since hundreds of lncRNAs are found to be associated with chromatin-modifying complexes, it is likely that this is one of the major mechanisms of lncRNAs-mediated gene regulation. However, it is still not known how some lncRNAs exert their effects in cis while others in trans. A few lncRNAs have been shown to exert their effects by associating with transcription factors and blocking their ability to bind specific genomic regions, and thus acting as decoys. Also, emerging evidence suggest that lncRNA can interact with microRNAs and act as ‘‘sponges’’ to block their ability to bind mRNAs. Finally, some lncRNAs are involved in the organization of cellular structures such as speckles and paraspeckles. The range of functions and mecha- nisms of lncRNAs is likely to be very diverse as discussed in the chapters of this book. In this book, we have gathered a number of the world’s experts on lncRNA to discuss new and exciting discoveries emerging from this new field. Topics range from the role of lncRNA in chromatin function, to possibilities of lncRNAs in disease. We also have discussions of lncRNAs outside mammalian organisms and highlight some of the new technologies that have come online to help study novel RNA transcripts. The lncRNA field is new and thus has the potential to be vast. We hope that the collected work, however, will provide the reader with an overview of what is known about lncRNAs and perhaps inspire new endeavors into this fascinating field. Ahmad M. Khalil Jeff Coller Contents Chromatin Regulation by Long Non-coding RNAs ............... 1 Daniel C. Factor, Paul J. Tesar and Ahmad M. Khalil Regulation of Eukaryotic Cell Differentiation by Long Non-coding RNAs ................................ 15 Juan R. Alvarez-Dominguez, Wenqian Hu and Harvey F. Lodish Roles of Long Non-coding RNAs in X-Chromosome Inactivation..... 69 J. Mauro Calabrese and Terry Magnuson Roles of Long Non-coding RNAs in Genomic Imprinting .......... 95 Kristen Martins-Taylor and Stormy J. Chamberlain Dysregulation of Long Non-coding RNAs in Human Disease ........ 115 Nianwei Lin and Tariq M. Rana Functions of Long Non-coding RNAs in Non-mammalian Systems................................ 137 Alex Tuck and David Tollervey Emerging Technologies to Study Long Non-coding RNAs .......... 163 Fereshteh Jahaniani, Varsha Rao, Stephanie Nevins, Damek Spacek, Neal Bharadwaj, Jason Reuter and Michael Snyder Long Non-coding RNAs and Nuclear Body Formation and Function .................................. 197 Ellen Fortini, Ruohan Li and Archa H. Fox Index ................................................ 217 vii Contributors Juan R. Alvarez-Dominguez Department of Biology, Whitehead Institute for Biomedical Research, Cambridge, MA, USA Neal Bharadwaj Department of Genetics, Stanford University, Stanford, CA, USA J. Mauro Calabrese Department of Genetics, Carolina Center for Genome Sci- ences and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC, USA Stormy Chamberlain Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT, USA Daniel C. Factor Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA Ellen Fortini Centre for Medical Research, Western Australian Institute for Medical Research, The University of Western Australia, Crawley, WA, Australia Archa H. Fox Centre for Medical Research, Western Australian Institute for Medical Research, The University of Western Australia, Crawley, WA, Australia Wenqian Hu Whitehead Institute for Biomedical Research, Cambridge, MA, USA Fereshteh Jahaniani Department of Genetics, Stanford University, Stanford, CA, USA Ruohan Li Centre for Medical Research, Western Australian Institute for Med- ical Research, The University of Western Australia, Crawley, WA, Australia Nianwei Lin Program for RNA Biology, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA Harvey F. Lodish Department of Biology, Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Department of Bioengineering, Massachusetts Institute of Technology, Cambridge, MA, USA ix x Contributors Terry Magnuson Department of Genetics, Carolina Center for Genome Sciences and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC, USA Kristen Martins-Taylor Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT, USA Stephanie Nevins Department of Genetics, Stanford University, Stanford, CA, USA Tariq
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