Bromodomain analysis of Brd2-dependent transcriptional activation of cyclin A.
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.
Sinha
Anupama
A
Cancer Research Center, Boston University School of Medicine, 80 East Concord Street, K521, Boston, MA 02118, USA.
Faller
Douglas V
DV
Denis
Gerald V
GV
D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation / Q000379:methods; D002868:Chromosomal Proteins, Non-Histone; D019925:Cyclin A / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000502:physiology; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D051548:Histone Acetyltransferases; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000196:embryology / Q000201:enzymology; D051379:Mice; D041681:NIH 3T3 Cells; D010770:Phosphotransferases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000502:physiology; D014157:Transcription Factors / Q000172:deficiency / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology*; D000092468:Bromodomain Containing Proteins
D000123:Acetyltransferases; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D019925:Cyclin A; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D051548:Histone Acetyltransferases; D010770:Phosphotransferases; D017346:Protein Serine-Threonine Kinases; D016160:Retinoblastoma Protein; D014157:Transcription Factors; C490844:Brd2 protein, mouse; D000092468:Bromodomain Containing Proteins; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse