title: FOXP3 orchestrates H4K16 acetylation and H3K4 trimethylation for activation of multiple genes by recruiting MOF and causing displacement of PLU-1.
abstract: Both H4K16 acetylation and H3K4 trimethylation are required for gene activation. However, it is still largely unclear how these modifications are orchestrated by transcriptional factors. Here, we analyzed the mechanism of the transcriptional activation by FOXP3, an X-linked suppressor of autoimmune diseases and cancers. FOXP3 binds near transcriptional start sites of its target genes. By recruiting MOF and displacing histone H3K4 demethylase PLU-1, FOXP3 increases both H4K16 acetylation and H3K4 trimethylation at the FOXP3-associated chromatins of multiple FOXP3-activated genes. RNAi-mediated silencing of MOF reduced both gene activation and tumor suppression by FOXP3, while both somatic mutations in clinical cancer samples and targeted mutation of FOXP3 in mouse prostate epithelial cells disrupted nuclear localization of MOF. Our data demonstrate a pull-push model in which a single transcription factor orchestrates two epigenetic alterations necessary for gene activation and provide a mechanism for somatic inactivation of the FOXP3 protein function in cancer cells.
authors.affiliation: Division of Immunotherapy, Department of Surgery, University of Michigan School of Medicine and Cancer Center, Ann Arbor, MI 48109, USA.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Katoh
authors.forename: Zhaohui S
authors.initials: ZS
authors.lastname: Qin
authors.forename: Runhua
authors.initials: R
authors.lastname: Liu
authors.forename: Lizhong
authors.initials: L
authors.lastname: Wang
authors.forename: Weiquan
authors.initials: W
authors.lastname: Li
authors.forename: Xiangzhi
authors.initials: X
authors.lastname: Li
authors.forename: Lipeng
authors.initials: L
authors.lastname: Wu
authors.forename: Zhanwen
authors.initials: Z
authors.lastname: Du
authors.forename: Robert
authors.initials: R
authors.lastname: Lyons
authors.forename: Chang-Gong
authors.initials: CG
authors.lastname: Liu
authors.forename: Xiuping
authors.initials: X
authors.lastname: Liu
authors.forename: Yali
authors.initials: Y
authors.lastname: Dou
authors.forename: Pan
authors.initials: P
authors.lastname: Zheng
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000107:Acetylation; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D008745:Methylation; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006657:Histones; D009687:Nuclear Proteins; D012097:Repressor Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human; D051548:Histone Acetyltransferases; C496552:KAT8 protein, human