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Molecular and Cellular Biology, February 2006, p. 1156-1164, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.1156-1164.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Mechanism of Polymerase II Transcription Repression by the Histone Variant macroH2A

Cécile-Marie Doyen,^1,2,6, Woojin An,^3,, Dimitar Angelov,^2,6 Vladimir Bondarenko,⁴ Flore Mietton,¹ Vassily M. Studitsky,⁴ Ali Hamiche,⁵ Robert G. Roeder,³ Philippe Bouvet,^2,6* and Stefan Dimitrov^1,2*

Institut Albert Bonniot, INSERM U309, 38706 La Tronche cedex, France,¹ Ecole Normale Supérieure de Lyon, Laboratoire Joliot Curie, 46 Allée d'Italie, 69007 Lyon, France,² Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, New York 10021,³ Department of Pharmacology, University of Medicine and Dentistry of New Jersey, 675 Hoes Lane, Piscataway, New Jersey 08854,⁴ Institut Andre Lwoff, CNRS UPR 9079, 7 rue Guy Moquet, 94800 Villejuif, France,⁵ Ecole Normale Supérieure de Lyon, LBMC, CNRS-UMR 5161, 46 Allée d'Italie, 69007 Lyon, France⁶

Received 29 July 2005/ Returned for modification 24 August 2005/ Accepted 3 November 2005

macroH2A (mH2A) is an unusual histone variant consisting of a histone H2A-like domain fused to a large nonhistone region. In this work, we show that histone mH2A represses p300- and Gal4-VP16-dependent polymerase II transcription, and we have dissected the mechanism by which this repression is realized. The repressive effect of mH2A is observed at the level of initiation but not at elongation of transcription, and mH2A interferes with p300-dependent histone acetylation. The nonhistone region of mH2A is responsible for both the repression of initiation of transcription and the inhibition of histone acetylation. In addition, the presence of this domain of mH2A within the nucleosome is able to block nucleosome remodeling and sliding of the histone octamer to neighboring DNA segments by the remodelers SWI/SNF and ACF. These data unambiguously identify mH2A as a strong transcriptional repressor and show that the repressive effect of mH2A is realized on at least two different transcription activation chromatin-dependent pathways: histone acetylation and nucleosome remodeling.

These authors contributed equally to this work.

Present address: Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, 1501 San Pablo Street, ZNI 241, MC 2821, Los Angeles, CA 90089-2821.

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