title: Opposing Roles for the lncRNA Haunt and Its Genomic Locus in Regulating HOXA Gene Activation during Embryonic Stem Cell Differentiation.
abstract: Long noncoding RNAs (lncRNAs) have been implicated in controlling various aspects of embryonic stem cell (ESC) biology, although the functions of specific lncRNAs, and the molecular mechanisms through which they act, remain unclear. Here, we demonstrate discrete and opposing roles for the lncRNA transcript Haunt and its genomic locus in regulating the HOXA gene cluster during ESC differentiation. Reducing or enhancing Haunt expression, with minimal disruption of the Haunt locus, led to upregulation or downregulation of HOXA genes, respectively. In contrast, increasingly large genomic deletions within the Haunt locus attenuated HOXA activation. The Haunt DNA locus contains potential enhancers of HOXA activation, whereas Haunt RNA acts to prevent aberrant HOXA expression. This work reveals a multifaceted model of lncRNA-mediated transcriptional regulation of the HOXA cluster, with distinct roles for a lncRNA transcript and its genomic locus, while illustrating the power of rapid CRISPR/Cas9-based genome editing for assigning lncRNA functions.
authors.affiliation: Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China; School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Yafei
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Pixi
authors.initials: P
authors.lastname: Yan
authors.affiliation: Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Pharmacology and Molecular Sciences and the HiT Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Guang
authors.initials: G
authors.lastname: Song
authors.affiliation: Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Li
authors.affiliation: Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China; Bioinformatics Research Group, Institute of Computing Technology, Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of Nanjing University, National Resource Center for Mutant Mice, Nanjing, Jiangsu 210061, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Shen
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of Nanjing University, National Resource Center for Mutant Mice, Nanjing, Jiangsu 210061, China.
authors.forename: Xingxu
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Pharmacology and Molecular Sciences and the HiT Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Heng
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Division of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.affiliation: Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China. Electronic address: xshen@tsinghua.edu.cn.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Shen
mesh_terms: D000818:Animals; D064113:CRISPR-Cas Systems; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D004247:DNA / Q000235:genetics; D053595:Embryonic Stem Cells / Q000502:physiology*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005786:Gene Expression Regulation; D056426:Genetic Loci / Q000235:genetics; D016678:Genome; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D018398:Homeodomain Proteins; D062085:RNA, Long Noncoding; C088144:HoxA protein; D004247:DNA