Bromodomain analysis of Brd2-dependent transcriptional activation of cyclin A.
Journal: 2005/July - Biochemical Journal
ISSN: 1470-8728
Abstract:
Cyclin A is regulated primarily through transcription control during the mammalian cell cycle. A dual mechanism of cyclin A transcriptional repression involves, on the one hand, promoter-bound inhibitory complexes of E2F transcription factors and RB (retinoblastoma) family proteins, and on the other, chromatin-directed histone deacetylase activity that is recruited to the cyclin A promoter early in the cell cycle in association with these RB proteins. This dual regulation maintains transcriptional silence of the cyclin A locus until its transcription is required in S-phase. At that time, RB family members dissociate from E2F proteins and nucleosomal restructuring of the locus takes place, to permit transcriptional activation and resultant S-phase progression to proceed. We have identified a double bromo-domain-containing protein Brd2, which exhibits apparent 'scaffold' or transcriptional adapter functions and mediates recruitment of both E2F transcription factors and chromatin-remodelling activity to the cyclin A promoter. We have shown previously that Brd2-containing nuclear, multiprotein complexes contain E2F-1 and -2. In the present study, we show that, in S-phase, they also contain histone H4-directed acetylase activity. Overexpression of Brd2 in fibroblasts accelerates the cell cycle through increased expression of cyclin A and its associated cyclin-dependent kinase activity. Chromatin immunoprecipitation studies show that Brd2 is physically present at the cyclin A promoter and its overexpression promotes increased histone H4 acetylation at the promoter as it becomes transcriptionally active, suggesting a new model for the dual regulation of cyclin A.
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Biochem J 387(Pt 1): 257-269

Bromodomain analysis of Brd2-dependent transcriptional activation of <em>cyclin A</em><sup>1</sup>

Cancer Research Center, Boston University School of Medicine, 80 East Concord Street, K521, Boston, MA 02118, U.S.A.
This work is dedicated to the memory of Susan C. Eaton, who died of acute myeloid leukaemia on 30 December 2003.
To whom correspondence should be addressed (email ude.ub@sinedg).
Received 2004 Oct 25; Accepted 2004 Nov 17.

Abstract

Cyclin A is regulated primarily through transcription control during the mammalian cell cycle. A dual mechanism of cyclin A transcriptional repression involves, on the one hand, promoter-bound inhibitory complexes of E2F transcription factors and RB (retinoblastoma) family proteins, and on the other, chromatin-directed histone deacetylase activity that is recruited to the cyclin A promoter early in the cell cycle in association with these RB proteins. This dual regulation maintains transcriptional silence of the cyclin A locus until its transcription is required in S-phase. At that time, RB family members dissociate from E2F proteins and nucleosomal restructuring of the locus takes place, to permit transcriptional activation and resultant S-phase progression to proceed. We have identified a double bromo-domain-containing protein Brd2, which exhibits apparent ‘scaffold’ or transcriptional adapter functions and mediates recruitment of both E2F transcription factors and chromatin-remodelling activity to the cyclin A promoter. We have shown previously that Brd2-containing nuclear, multiprotein complexes contain E2F-1 and -2. In the present study, we show that, in S-phase, they also contain histone H4-directed acetylase activity. Overexpression of Brd2 in fibroblasts accelerates the cell cycle through increased expression of cyclin A and its associated cyclin-dependent kinase activity. Chromatin immunoprecipitation studies show that Brd2 is physically present at the cyclin A promoter and its overexpression promotes increased histone H4 acetylation at the promoter as it becomes transcriptionally active, suggesting a new model for the dual regulation of cyclin A.

Keywords: bromodomain, cell cycle, chromatin, cyclin A, histone acetylase, transcription
Abbreviations: BrdU, bromodeoxyuridine; CBP, CREB-binding protein; cdk, cyclin-dependent kinase; ChIP, chromatin immunoprecipitation; CMV, cytomegalovirus; CREB, cAMP-response-element-binding protein; DMEM, Dulbecco's modified Eagle's medium; DTT, dithiothreitol; FBS, fetal bovine serum; HA, haemagglutinin; HAT, histone acetyltransferase; HDAC, histone deacetylase; PSG, penicillin, streptomycin and glutamine; RB, retinoblastoma; NP40, Nonidet P40; PKA, protein kinase A; WT, wild-type
Abstract

Acknowledgments

We thank J.M. Blanchard (Institut de Génétique Moléculaire, Montpellier, France) for the cyclin A reporter, F. J. Giordano (Yale University, New Haven, CT, U.S.A.) for adenovirus expression plasmids, H. Cohen (Boston University School of Medicine, Boston, MA, U.S.A.) for 293T cells, C. Vaziri (Boston University School of Medicine) for help with adenovirus technology (including green fluorescent protein-expressing adenovirus), R. Sternglanz (Stony Brook University, New York, NY, U.S.A.) for an expression vector for recombinant yeast Gcn5, D. McDevit (Boston University School of Medicine) for help with ChIP and J. Tumang (Boston University School of Medicine) for help with real-time PCR. We thank members of the Cancer Research Center, B. Nikolajczyk and T. Rothstein of the Immunobiology Unit, both at Boston University School of Medicine, and G. Schnitzler of Tufts University School of Medicine for helpful criticism. This work was supported by United States Public Health Service grants CA84193 (D.V.F.), CA75107 and {"type":"entrez-nucleotide","attrs":{"text":"CA102889","term_id":"34956196","term_text":"CA102889"}}CA102889 (G.V.D.) from the National Cancer Institute.

Acknowledgments

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