title: Brd4 links chromatin targeting to HPV transcriptional silencing.
abstract: The E2 protein encoded by human papillomaviruses (HPVs) inhibits expression of the viral E6 oncoprotein, which, in turn, regulates p53 target gene transcription. To identify cellular proteins involved in E2-mediated transcriptional repression, we isolated an E2 complex from human cells conditionally expressing HPV-11 E2. Surprisingly, the double bromodomain-containing protein Brd4, which is implicated in cell cycle control and viral genome segregation, was found associated with E2 and conferred on E2 the ability to inhibit AP-1-dependent HPV chromatin transcription in an E2-binding site-specific manner as illustrated by in vitro reconstituted chromatin transcription experiments. Knockdown of Brd4 in human cells alleviates E2-mediated repression of HPV transcription. The E2-interacting domain at the extreme C terminus and the chromatin targeting activity of a bromodomain-containing region are both essential for the corepressor activity of Brd4. Interestingly, E2-Brd4 blocks the recruitment of TFIID and RNA polymerase II to the HPV E6 promoter region without inhibiting acetylation of nucleosomal histones H3 and H4, indicating an acetylation-dependent role of Brd4 in the recruitment of E2 for transcriptional silencing of HPV gene activity. Our finding that Brd4 is a component of the virus-assembled transcriptional silencing complex uncovers a novel function of Brd4 as a cellular cofactor modulating viral gene expression.
authors.affiliation: Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Shwu-Yuan
authors.initials: SY
authors.lastname: Wu
authors.forename: A-Young
authors.initials: AY
authors.lastname: Lee
authors.forename: Samuel Y
authors.initials: SY
authors.lastname: Hou
authors.forename: Jongsook Kim
authors.initials: JK
authors.lastname: Kemper
authors.forename: Hediye
authors.initials: H
authors.lastname: Erdjument-Bromage
authors.forename: Paul
authors.initials: P
authors.lastname: Tempst
authors.forename: Cheng-Ming
authors.initials: CM
authors.lastname: Chiang
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral; D020868:Gene Silencing; D018390:Gene Targeting; D006367:HeLa Cells; D052140:Human papillomavirus 11 / Q000235:genetics* / Q000378:metabolism; D052161:Human papillomavirus 18 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D014764:Viral Proteins; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C486694:Brd4 protein, mouse; C117355:E2 protein, Human papillomavirus type 11