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J. Biol. Chem., Vol. 283, Issue 14, 9040-9048, April 4, 2008

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The Bromodomain Protein Brd4 Stimulates G₁ Gene Transcription and Promotes Progression to S Phase^*

From the Laboratory of Molecular Growth Regulation, NICHD, National Institutes of Health, Bethesda, Maryland 20892

Brd4 is a bromodomain protein that binds to acetylated chromatin. It regulates cell growth, although the underlying mechanism has remained elusive. Brd4 has also been shown to control transcription of viral genes, whereas its role in transcription of cellular genes has not been fully elucidated. Here we addressed the role of Brd4 in cell growth and transcription using a small hairpin (sh) RNA approach. The Brd4 shRNA vector stably knocked down Brd4 protein expression by 90% in NIH3T3 cells and mouse embryonic fibroblasts. Brd4 knockdown cells were growth impaired and grew more slowly than control cells. When synchronized by serum starvation and released, Brd4 knockdown cells were arrested at G₁, whereas control cells progressed to S phase. In microarray analysis, although numerous genes were up-regulated during G₁ in control cells, many of these G₁ genes were not up-regulated in Brd4 knockdown cells. Reintroduction of Brd4 rescued expression of these G₁ genes in Brd4 knockdown cells, allowing cells to progress toward S phase. Chromatin immunoprecipitation analysis showed that Brd4 was recruited to the promoters of these G₁ genes during G₀-G₁ progression. Furthermore, Brd4 recruitment coincided with increased binding of Cdk9, a component of P-TEFb and RNA polymerase II to these genes. Brd4 recruitment was low to absent at genes not affected by Brd4 shRNA. The results indicate that Brd4 stimulates G₁ gene expression by binding to multiple G₁ gene promoters in a cell cycle-dependent manner.

Received for publication, September 11, 2007 , and in revised form, January 17, 2008.

^* This work was supported in part by the Intramural Program of NICHD, National Institutes of Health, and the Intramural AIDS targeted antiviral program (IATAP) program of National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Figs. S1-S5.

¹ These authors made equal contributions to this work.

² Supported in part by a Japan Society for Promotion of Science fellowship. Present address: Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.

³ Present address: Laboratory of Genetics, NIA, NIH, Baltimore, MD 21224.

⁴ Present address: Laboratory of Viral Diseases, NIAID, NIH, Bethesda, MD 20892.

⁵ Present address: Dept. of Immunology, Tokyo University, Bunkyo-ku, Tokyo 113-0033, Japan.

⁶ Present address: Hamamatsu University, School of Medicine, Hamamatsu 431-3192, Japan.

⁷ Present address: Pennsylvania State University College of Medicine, Hershey, PA 17033.

⁸ To whom correspondence should be addressed: Laboratory of Molecular Growth Regulation, NICHD, National Institutes of Health, Bldg. 6, Rm. 2A01, 6 Center Dr., Bethesda MD 20892-2753. Tel.: 301-496-9184; Fax: 301-402-2974; E-mail: ozatok{at}nih.gov.

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