title: BRAD4 plays a critical role in germinal center response by regulating Bcl-6 and NF-κB activation.
abstract: Germinal center (GC) reaction is a T cell-dependent process in which activated B cells undergo clonal expansion and functional maturation to produce high affinity antibodies and differentiate into memory B cells(1). Here we demonstrate a new role of bromodomain and extraterminal domain (BET) protein BRD4 in GC B cell development. We found that during B cell differentiation stage there was an elevated expression of BRD4 in GC B cells and inhibition of BRD4 by small molecule inhibitors led to the suppression of GC formation and correspondent antibody responses in a Td antigen immunization model. At the molecular level, we found that the effects of BRD4 in primary GC B cell differentiation and B cell lymphoma were mediated through the impaired phosphorylation and translocation of NF-κBp65 and further down-regulation of B-cell lymphoma 6 (Bcl6) expression. Thus this study reveals a novel function of BRD4 in controlling the GC B cell development pathway.
authors: Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China.
authors: Fangjie
authors: F
authors: Gao
authors: Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China.
authors: Yuanyuan
authors: Y
authors: Yang
authors: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China. Electronic address: zywang01@sibs.ac.cn.
authors: Zhengyi
authors: Z
authors: Wang
authors: Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China. Electronic address: xmgao@suda.edu.cn.
authors: Xiaoming
authors: X
authors: Gao
authors: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: bzheng@bcm.edu.
authors: Biao
authors: B
authors: Zheng
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood / Q000276:immunology; D001381:Azepines / Q000494:pharmacology; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D050976:Basic-Leucine Zipper Transcription Factors / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D018858:Germinal Center / Q000276:immunology*; D006801:Humans; D050835:Interferon Regulatory Factors / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D009698:Nucleoproteins / Q000276:immunology; D051757:PAX5 Transcription Factor / Q000096:biosynthesis; D010766:Phosphorylation; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000276:immunology; D051996:Transcription Factor RelA / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014230:Triazoles / Q000494:pharmacology; D000099185:Interferon Regulatory Factor-8; D000092468:Bromodomain Containing Proteins
chemical_list: D000906:Antibodies; D001381:Azepines; D050976:Basic-Leucine Zipper Transcription Factors; D018797:Cell Cycle Proteins; D050835:Interferon Regulatory Factors; D009687:Nuclear Proteins; D009698:Nucleoproteins; D051757:PAX5 Transcription Factor; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014230:Triazoles; D000099185:Interferon Regulatory Factor-8; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C102109:Bach2 protein, mouse; C486694:Brd4 protein, mouse; C497282:Pax5 protein, mouse; C498144:Rela protein, mouse
keywords: Antibody responses; BRD4; Bcl6; Germinal center B cells