title: Genome-wide Analysis Identifies Bcl6-Controlled Regulatory Networks during T Follicular Helper Cell Differentiation.
abstract: T follicular helper (Tfh) cell is a unique T cell subset specialized in promoting humoral immunity. B-cell lymphoma 6 protein (Bcl6) has been identified as an obligatory transcription factor in Tfh cells; however, the molecular mechanism underlying Bcl6 function remains largely unknown. Here, we defined Bcl6 target genes in Tfh cells by analyzing genome-wide Bcl6 occupancy together with transcriptome profiling. With consensus sequences being different from those in Th9, B cells, and macrophages, Bcl6 binding in Tfh cell was closely associated with a decrease in 5-hydroxymethylcytosine (5hmC). Importantly, Bcl6 promoted Tfh cell differentiation through antagonizing IL-7R (CD127)/signal transducer and activator of transcription (STAT) 5 axis; deletion of the Bcl6 gene in T cells resulted in enhanced IL-7R-STAT5 signaling and substantial expansion of CD127(hi) non-Tfh cells. Thus, our study systemically examines Bcl6-controlled regulatory networks and provides important insights into Bcl6's biological functions in Tfh cells.
authors.affiliation: Tsinghua University Institute for Immunology and School of Medicine, Beijing 100084, China; Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Xindong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Tsinghua University Institute for Immunology and School of Medicine, Beijing 100084, China.
authors.forename: Huiping
authors.initials: H
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Immunology, MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Kalyan C
authors.initials: KC
authors.lastname: Nallaparaju
authors.affiliation: Institute for Systems Biology, Seattle, WA 98103, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Yan
authors.affiliation: Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Immunology, MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ichiyama
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Computational Biology and Bioinformatics, MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Wen
authors.affiliation: Institute for Systems Biology, Seattle, WA 98103, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Tian
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Xiu-Wu
authors.initials: XW
authors.lastname: Bian
authors.affiliation: Tsinghua University Institute for Immunology and School of Medicine, Beijing 100084, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China. Electronic address: weil9@mail.sysu.edu.cn.
authors.forename: Lai
authors.initials: L
authors.lastname: Wei
authors.affiliation: Tsinghua University Institute for Immunology and School of Medicine, Beijing 100084, China. Electronic address: chendong@tsinghua.edu.cn.
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D001483:Base Sequence; D002454:Cell Differentiation; D003596:Cytosine / Q000031:analogs & derivatives / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000276:immunology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000276:immunology*; D055106:Genome-Wide Association Study; D018858:Germinal Center / Q000166:cytology / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D051560:Proto-Oncogene Proteins c-bcl-6; D020395:Receptors, Interleukin-7 / Q000235:genetics* / Q000276:immunology; D050799:STAT5 Transcription Factor / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D007378:Interleukins; D051560:Proto-Oncogene Proteins c-bcl-6; D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; C011865:5-hydroxymethylcytosine; D015847:Interleukin-4; D044503:5-Methylcytosine; D003596:Cytosine; D000098546:Interleukin-21