title: A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression.
abstract: The genome is extensively transcribed into long intergenic noncoding RNAs (lincRNAs), many of which are implicated in gene silencing. Potential roles of lincRNAs in gene activation are much less understood. Development and homeostasis require coordinate regulation of neighbouring genes through a process termed locus control. Some locus control elements and enhancers transcribe lincRNAs, hinting at possible roles in long-range control. In vertebrates, 39 Hox genes, encoding homeodomain transcription factors critical for positional identity, are clustered in four chromosomal loci; the Hox genes are expressed in nested anterior-posterior and proximal-distal patterns colinear with their genomic position from 3' to 5'of the cluster. Here we identify HOTTIP, a lincRNA transcribed from the 5' tip of the HOXA locus that coordinates the activation of several 5' HOXA genes in vivo. Chromosomal looping brings HOTTIP into close proximity to its target genes. HOTTIP RNA binds the adaptor protein WDR5 directly and targets WDR5/MLL complexes across HOXA, driving histone H3 lysine 4 trimethylation and gene transcription. Induced proximity is necessary and sufficient for HOTTIP RNA activation of its target genes. Thus, by serving as key intermediates that transmit information from higher order chromosomal looping into chromatin modifications, lincRNAs may organize chromatin domains to coordinate long-range gene activation.
authors.affiliation: Howard Hughes Medical Institute, Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Wang
authors.forename: Yul W
authors.initials: YW
authors.lastname: Yang
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: Amartya
authors.initials: A
authors.lastname: Sanyal
authors.forename: Ryan
authors.initials: R
authors.lastname: Corces-Zimmerman
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Lajoie
authors.forename: Angeline
authors.initials: A
authors.lastname: Protacio
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Flynn
authors.forename: Rajnish A
authors.initials: RA
authors.lastname: Gupta
authors.forename: Joanna
authors.initials: J
authors.lastname: Wysocka
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.forename: Job
authors.initials: J
authors.lastname: Dekker
authors.forename: Jill A
authors.initials: JA
authors.lastname: Helms
authors.forename: Howard Y
authors.initials: HY
authors.lastname: Chang
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D021901:DNA, Intergenic / Q000235:genetics; D004622:Embryo, Mammalian / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D055785:Gene Knockdown Techniques; D005801:Genes, Homeobox / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics; D009928:Organ Specificity; D022661:RNA, Untranslated / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D021901:DNA, Intergenic; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D022661:RNA, Untranslated; C502547:WDR5 protein, human; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine