Issue title: Including special section: Abstracts from the 2013 World Congress on Huntington's Disease
Article type: Research Article
Authors: McFarland, Karen N. | Das, Sudeshna | Sun, Ting Ting | Leyfer, Dmitri | Kim, Mee-Ohk | Xia, Eva | Sangrey, Gavin R. | Kuhn, Alexandre | Luthi-Carter, Ruth; | Clark, Timothy W. | Sadri-Vakili, Ghazaleh | Cha, Jang-Ho J.
Affiliations: Department of Neurology, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA | MIND Informatics, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Cambridge, MA, USA | Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland | Department of Cell Physiology and Pharmacology, College of Medicine, University of Leicester, Leicester, UK
Note: [] Current Address: Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL 32611, USA.
Note: [] Current Address: The Broad Institute, Cambridge, MA 02142, USA.
Note: [] Correspondence to: Jang-Ho J. Cha, Merck & Co., Inc., 351 N. Summmney town Pike, Mailstop UG4D-48, North Wales, PA 19454, USA. Tel.: +1 267 305 3088; Fax: +1 267 305 6447; E-mail: j.cha@merck.com
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.
Keywords: Huntington's disease, transcriptional regulation, histone ubiquitylation, R6/2 mouse
DOI: 10.3233/JHD-130066
Journal: Journal of Huntington's Disease, vol. 2, no. 3, pp. 263-277, 2013
