title: Psip1/p52 regulates posterior Hoxa genes through activation of lncRNA Hottip.
abstract: Long noncoding RNAs (lncRNAs) have been implicated in various biological functions including the regulation of gene expression, however, the functionality of lncRNAs is not clearly understood and conflicting conclusions have often been reached when comparing different methods to investigate them. Moreover, little is known about the upstream regulation of lncRNAs. Here we show that the short isoform (p52) of a transcriptional co-activator-PC4 and SF2 interacting protein (Psip1), which is known to be involved in linking transcription to RNA processing, specifically regulates the expression of the lncRNA Hottip-located at the 5' end of the Hoxa locus. Using both knockdown and knockout approaches we show that Hottip expression is required for activation of the 5' Hoxa genes (Hoxa13 and Hoxa10/11) and for retaining Mll1 at the 5' end of Hoxa. Moreover, we demonstrate that artificially inducing Hottip expression is sufficient to activate the 5' Hoxa genes and that Hottip RNA binds to the 5' end of Hoxa. By engineering premature transcription termination, we show that it is the Hottip lncRNA molecule itself, not just Hottip transcription that is required to maintains active expression of posterior Hox genes. Our data show a direct role for a lncRNA molecule in regulating the expression of developmentally-regulated mRNA genes in cis.
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at University of Edinburgh, Edinburgh, United Kingdom.|School of biological sciences, University of Essex, Colchester, United Kingdom.
authors.forename: Madapura M
authors.initials: MM
authors.lastname: Pradeepa
authors.affiliation: School of biological sciences, University of Essex, Colchester, United Kingdom.
authors.forename: Fionnuala
authors.initials: F
authors.lastname: McKenna
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Gillian C A
authors.initials: GC
authors.lastname: Taylor
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Hemant
authors.identifier: 0000-0002-3370-8326
authors.initials: H
authors.lastname: Bengani
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Graeme R
authors.initials: GR
authors.lastname: Grimes
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Andrew J
authors.identifier: 0000-0002-0653-2070
authors.initials: AJ
authors.lastname: Wood
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Shipra
authors.initials: S
authors.lastname: Bhatia
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Wendy A
authors.identifier: 0000-0001-6660-7735
authors.initials: WA
authors.lastname: Bickmore
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D062085:RNA, Long Noncoding / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; C504649:PSIP1 protein, human; D062085:RNA, Long Noncoding; D014157:Transcription Factors; C099959:homeobox protein HOXA13; C000613830:long noncoding RNA HOTTIP, human; C069634:HOXA10 protein, human