A Hox Embedded Long Noncoding RNA: Is It All Hot Air?
PERSPECTIVE A Hox Embedded Long Noncoding RNA: Is It All Hot Air? Licia Selleri 1 Marisa S. Bartolomei 2 Wendy A. Bickmore 3 Lin He 4 Lisa Stubbs 5 Wolf Reik 6 Gregory S. Barsh 7,8 1 Program in Craniofacial Biology; Institute of Human Genetics; Eli and Edythe Broad Center of Regeneration Medicine Stem Cell Research; Department of Orofacial Sciences Department of Anatomy; University of California San Francisco, San Francisco, California, United States of America, 2 Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America, 3 Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom, 4 Division of Cellular and Developmental Biology, University of California Berkeley, Berkeley, California, United States of America, 5 Institute for Genomic Biology, Department of Cell and Developmental Biology, University of Illinois, Urbana, Illinois, United States of America, 6 Department of Epigenetics, The Babraham Institute, Cambridge, United Kingdom, 7 HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, United States of America, 8 Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America Licia.Selleri@ucsf.edu (LSE) gbarsh@hudsonalpha.org (GSB) a11111 OPEN ACCESS Citation: Selleri L, Bartolomei MS, Bickmore WA, He L, Stubbs L, Reik W, et al. (2016) A Hox Embedded Long Noncoding RNA: Is It All Hot Air? PLoS Genet 12(12) e1006485. doi:10.1371/ journal.pgen.1006485 Editor: Gregory P. Copenhaver, The University of North Carolina at Chapel Hill, UNITED STATES Published: December 15, 2016 Copyright: (c) 2016 Selleri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: No specific funding was received for this article. Competing Interests: GSB is an Editor in Chief of PLOS Genetics. WAB and WR are Section Editors for the Epigenetics Section for PLOS Genetics. LSe, MSB, LH, and LSt are Associate Editors for PLOS Genetics. Over 20 years ago, the discovery of Xist as a critical component of X chromosome inactivation revealed a fundamental role for long noncoding RNAs (lncRNAs) in epigenetic regulation during mammalian development and foreshadowed a fascinating connection between RNA and chromatin modification [1 3] In the last decade, the field has exploded, heralded in part by a 2007 landmark paper from the group of Howard Chang [4] describing that knockdown of a lncRNA (Hox Antisense Intergenic RNA [HOTAIR] was associated with loss of transcrip tional repression from a locus on another chromosome in trans. HOTAIR lncRNA encoded within the HOXC locus, although its expression seemed to be required for normal epigenetic silencing of HOXD genes became one of the most well known examples of functional lncRNAs in the field of developmental epigenetics. Interest intensified when a subsequent paper from the Chang lab [5] reported that targeted deletion of the orthologous locus in the mouse (Hotair) caused homeotic transformations underpinned by derepression of HoxD gene transcription in vivo. Discovery of new lncRNAs and exploration of their potential actions and effects during development and disease is a continued source of excitement [6,7] But ques tions about the effects and actions of Hotair have been controversial, raised in part by work from the group of Denis Duboule [8] This debate is addressed directly in the current issue of PLOS Genetics in a manuscript from Duboule's laboratory [9] that reanalyzes Hotair mutant mice generated by the Chang lab, a formal comment in response to that manuscript from the Chang lab [10] and this perspective. A precise genomic organization conserved for hundreds of millions of years underlies the complexity of Hox gene regulation. Expression of adjacent Hox genes in specific spatiotempo ral domains helps to pattern and maintain the identity of developmental compartments along the body and appendicular axes [8,11] It is the latter part of that equation maintenance of developmental identity for which genomic organization may be so important, and for which epigenetic mechanisms play a critical role, because specific patterns of Hox gene transcription can be faithfully maintained long after development has concluded, sometimes in cultured cells outside the body [12] PLOS Genetics DOI:10.1371/journal.pgen.1006485 December 15, 2016
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