title: Genome-wide increase in histone H2A ubiquitylation in a mouse model of Huntington's disease.
abstract: BACKGROUND
  Huntington's disease (HD) is a neurodegenerative disorder with selective vulnerability of striatal neurons and involves extensive transcriptional dysregulation early in the disease process. Previous work in cell and mouse models has shown that histone modifications are altered in HD. Specifically, monoubiquitylated histone H2A (uH2A) is present at the promoters of downregulated genes which led to the hypothesis that uH2A plays a role in transcriptional silencing in HD.
  
  
  OBJECTIVE
  To broaden our view of uH2A function in transcription in HD, we examined genome-wide binding sites of uH2A in 12-week old striatal tissue from R6/2 transgenic HD mouse model.
  
  
  METHODS
  We used chromatin immunoprecipitation followed by genomic promoter microarray hybridization (ChIP-chip) and then interrogated how these binding sites correlate with transcribed genes.
  
  
  RESULTS
  Our analysis reveals that, while uH2A levels are globally increased at the genome in the transgenic (TG) striatum, uH2A localization at a gene did not strongly correlate with the absence of its transcript. Furthermore, analysis of differential ubiquitylation in wild-type (WT) and TG striata did not reveal the expected enrichment of uH2A at genes with decreased expression in the TG striatum.
  
  
  CONCLUSIONS
  This first description of genome-wide localization of uH2A in an HD model reveals that monoubiquitylation of histone H2A may not function at the level of the individual gene but may rather influence transcription through global chromatin structure.
authors: Department of Neurology, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA.
authors: Karen N
authors: KN
authors: McFarland
authors: MIND Informatics, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Cambridge, MA, USA.
authors: Sudeshna
authors: S
authors: Das
authors: Department of Neurology, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA.
authors: Ting Ting
authors: TT
authors: Sun
authors: MIND Informatics, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Cambridge, MA, USA.
authors: Dmitri
authors: D
authors: Leyfer
authors: Department of Neurology, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA.
authors: Mee-Ohk
authors: MO
authors: Kim
authors: Department of Neurology, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA.
authors: Eva
authors: E
authors: Xia
authors: Department of Neurology, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA.
authors: Gavin R
authors: GR
authors: Sangrey
authors: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors: Alexandre
authors: A
authors: Kuhn
authors: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland Department of Cell Physiology and Pharmacology, College of Medicine, University of Leicester, Leicester, UK.
authors: Ruth
authors: R
authors: Luthi-Carter
authors: MIND Informatics, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Cambridge, MA, USA.
authors: Timothy W
authors: TW
authors: Clark
authors: Department of Neurology, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA.
authors: Ghazaleh
authors: G
authors: Sadri-Vakili
authors: Department of Neurology, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA.
authors: Jang-Ho J
authors: JH
authors: Cha
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D020868:Gene Silencing; D006657:Histones / Q000235:genetics* / Q000378:metabolism*; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D059467:Transcriptome; D054875:Ubiquitination; D014452:Ubiquitins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D006657:Histones; D014452:Ubiquitins; C021645:chromatin conjugate protein A24
keywords: Huntington's disease; R6/2 mouse; histone ubiquitylation; transcriptional regulation