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M.R.S. Rao Editor Long Non Coding RNA Biology Advances in Experimental Medicine and Biology Volume 1008 Advances in Experimental Medicine and Biology 1008 M.R.S. Rao Editor Long Non Coding RNA Biology Advances in Experimental Medicine and Biology Volume 1008 Editorial Board: IRUN R. COHEN, The Weizmann Institute of Science, Rehovot, Israel ABEL LAJTHA, N.S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA JOHN D. LAMBRIS, University of Pennsylvania, Philadelphia, PA, USA RODOLFO PAOLETTI, University of Milan, Milan, Italy More information about this series at http://www.springer.com/series/5584 M.R.S. Rao Editor Long Non Coding RNA Biology Editor M.R.S. Rao Molecular Biology and Genetics Unit Jawaharlal Nehru Centre for Advanced Scientific Research Bangalore India ISSN 0065-2598 ISSN 2214-8019 (electronic) Advances in Experimental Medicine and Biology ISBN 978-981-10-5202-6 ISBN 978-981-10-5203-3 (eBook) DOI 10.1007/978-981-10-5203-3 Library of Congress Control Number: 2017950052 © Springer Nature Singapore Pte Ltd. 2017 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. 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. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Printed on acid-free paper This Springer imprint is published by Springer Nature The registered company is Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore Foreword In recent years, our functional understanding of the genome has changed dramati- cally. The discovery of pervasive transcription and the prevalence of noncoding RNAs (ncRNAs) have challenged the traditional definition of genes and what should be considered a functional region of the genome. Noncoding RNAs are defined as transcripts that do not encode proteins. Formally, this classification includes compo- nents of the translation machinery such as ribosomal RNA (rRNA) and transfer RNA (tRNA). However, the term ncRNA is also commonly used to describe other noncoding transcripts implicated in the regulation of gene expression. In particular, this category includes short regulatory ncRNAs (e.g., microRNAs, small interfering RNA) and longer transcripts about which much less is known. This book focuses on this latter class of long ncRNAs (lncRNAs). The rise of modern genomics was fundamental for uncovering the diversity of lncRNAs, their omnipresence across the tree of life, and their varied mechanisms of action. lncRNAs regulate gene expression at all levels, from modifying the epigen- etic status of chromatin to modulating the stability of protein-coding mRNAs in the cytoplasm. Some lncRNAs exert their effects locally (e.g., by regulating the expres- sion of neighboring genes in cis), while others affect multiple loci across the genome. Sometimes the presence of an lncRNA is essential for its own functional impact. This is the case for lncRNAs acting as scaffolds for the assembly and recruitment of various functional elements to chromatin. In other situations, lncRNAs function through their own transcription. For example, antisense lncRNA transcripts (lncRNAs overlapping gene-coding regions on the opposite DNA strand) may inhibit or modulate the expression of the sense mRNA either by direct tran- scriptional interference or by recruiting chromatin modifiers. Thus, even if lncRNAs are constantly removed by the cellular machinery, they may still have a functional impact on the transcriptome through their generation. lncRNAs also have roles beyond chromatin. Some act as sponges sequestering diverse regulatory elements (e.g., miRNAs) and thus decreasing their impact on target mRNAs. Others modulate how the cell recognizes mRNA molecules and thus regulate translation efficiency, cellular localization, or stability. These examples illustrate the diverse mechanisms of action that lncRNAs use to regulate gene v vi Foreword expression. However, despite many examples describing functional roles of lncRNAs, for the vast majority, the mechanisms of action remain unknown. lncRNAs have been found in nearly all organisms studied, suggesting that they are a fundamental component of gene expression. Interestingly, the ratio of lncRNAs (in comparison to canonical mRNAs) is higher in more complex organisms, sug- gesting that they contribute to the increased regulatory complexity in higher eukary- otes. In budding yeast, it has been shown that lncRNA expression can result in chains of overlapping sense and antisense transcripts that lead to the rewiring of regulatory gene expression networks. This process, in which lncRNAs spread regu- latory signals across the genome, is thought to be even more complex in higher eukaryotes. Furthermore, the boundaries between coding and noncoding RNAs are often vague; in some cases, previously identified lncRNAs have been shown to encode short peptides with potential biological functions. This implies that lncRNAs may also serve as evolutionary intermediates for the generation of new genes. The last decade of genomics has revealed a surprising diversity of lncRNAs with diverse mechanisms of action. However, we have so far only seen the tip of the ice- berg in a whole new field of biology. In the coming years, the development of new tools such as high-throughput long-read sequencing promises to boost our ability to discover and characterize lncRNAs. The development of novel approaches to assay the functional impact of such lncRNAs will allow us to better understand their phe- notypic consequences and mechanisms of action. In addition, the detailed biochem- ical and molecular characterization of lncRNAs will be essential for our understanding of fundamental cell biology, evolution, health, and disease. Lars M. Steinmetz, PhD Professor of Genetics, Stanford University School of Medicine, Stanford, CA, USA Co-Director, Stanford Genome Technology Center, Stanford, CA, USA Principle Investigator and Senior Scientist, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany Vicent Pelechano, PhD Assistant Professor and SciLifeLab Fellow, Department of Microbiology, Tumor and Cell Biology, Science for Life Laboratory, Karolinska Institute, Solnavägen, Solna, Sweden Preface RNA has been an interesting molecule in biology displaying a multitude of func- tions in all cellular systems. According to the RNA world hypothesis, it is proposed that RNA was the first macromolecule to arise in the universe even before DNA and proteins came into existence. However, modern biology has seen a great influence of DNA as the information storage house, while the proteins are really the final functional actors in various cellular functions. RNA was thought to have only a sup- porting role in maintaining the functional homeostasis. Messenger RNA carries the information encoded in DNA. Ribosomal RNA organizes the ribosome structure to facilitate the translation of the messenger RNAs. Transfer RNAs carry the amino acids to be incorporated into the proteins. Other small RNA molecules like 5S RNA and 5.8S RNA contribute to ribosome function. Small nuclear and nucleolar RNAs (snRNAs and snoRNAs) play significant roles in splicing machinery. For a long period of time, it was a common notion that the entire DNA in eukaryotic cells is not transcribed, and the junk DNA hypothesis prevailed for a few decades. However, subsequent to the completion of the Human Genome Project and the advent of NGS technology, we have seen that much of the DNA is pervasively transcribed to gener- ate a large repertoire of RNA molecules which are now being classified as non-­­­ coding RNAs. This includes both short (22–33 nucleotides in length) and long RNA species (>200 nucleotides in length). Presently it is estimated that there are more genes coding for long noncoding RNA genes than the estimated ~25,000 protein-­­­ coding genes in humans and mice. It is becoming increasingly clear that long non- coding RNAs (lncRNAs) have ubiquitous biological function(s) in almost every aspect of cellular biology, regulating gene expression and contributing to the final functional output of protein-coding genes. lncRNAs are found in all eukaryotes from unicellular organisms to higher mammals. The present book is an attempt to briefly describe the most recent developments in the area of long noncoding RNA biology which is one of the emergent hot topics in the field of molecular and cellular biology today. The first chapter by Jarroux, Morillon, and Pinskaya introduces the area of lncRNAs beginning with the history and their discovery. This is followed by a description of their characteristic
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