title: Differential coupling of KLF10 to Sin3-HDAC and PCAF regulates the inducibility of the FOXP3 gene.
abstract: Inducible gene expression, which requires chromatin remodeling on gene promoters, underlies the epigenetically inherited differentiation program of most immune cells. However, chromatin-mediated mechanisms that underlie these events in T regulatory cells remain to be fully characterized. Here, we report that inducibility of FOXP3, a key transcription factor for the development of T regulatory cells, depends upon Kruppel-like factor 10 (KLF10) interacting with two antagonistic histone-modifying systems. We utilized chromatin immunoprecipitation, genome-integrated reporter assays, and functional domain KLF10 mutant proteins, to characterize reciprocal interactions between this transcription factor and either the Sin3-histone deacetylase complex or the histone acetyltransferase, p300/CBP-associated factor (PCAF). We characterize a Sin3-interacting repressor domain on the NH2 terminus of KLF10, which works to limit the activating function of this transcription factor. Indeed, inactivation of this Sin3-interacting domain renders KLF10 able to physically associate with PCAF as to induce FOXP3 gene transcription. We show that this biochemical data derived from studying our genome-integrated reporter cell system are recapitulated in primary murine lymphocytes. Collectively, these results advance our understanding of how a single transcription factor, namely KLF10, functions as a toggle to integrate antagonistic signals regulating FOXP3 and, thus, immune activation.
authors.affiliation: Epigenetics and Chromatin Dynamics Laboratory, Mayo Clinic, Rochester, Minnesota; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Yuning
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Epigenetics and Chromatin Dynamics Laboratory, Mayo Clinic, Rochester, Minnesota; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Svingen
authors.affiliation: Epigenetics and Chromatin Dynamics Laboratory, Mayo Clinic, Rochester, Minnesota; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Olga O
authors.initials: OO
authors.lastname: Sarmento
authors.affiliation: Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Smyrk
authors.affiliation: Epigenetics and Chromatin Dynamics Laboratory, Mayo Clinic, Rochester, Minnesota; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Maneesh
authors.initials: M
authors.lastname: Dave
authors.affiliation: Epigenetics and Chromatin Dynamics Laboratory, Mayo Clinic, Rochester, Minnesota; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Sahil
authors.initials: S
authors.lastname: Khanna
authors.affiliation: Epigenetics and Chromatin Dynamics Laboratory, Mayo Clinic, Rochester, Minnesota; Translational Epigenomic Program, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: Gwen A
authors.initials: GA
authors.lastname: Lomberk
authors.affiliation: Epigenetics and Chromatin Dynamics Laboratory, Mayo Clinic, Rochester, Minnesota; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Translational Epigenomic Program, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: Raul A
authors.initials: RA
authors.lastname: Urrutia
authors.affiliation: Epigenetics and Chromatin Dynamics Laboratory, Mayo Clinic, Rochester, Minnesota; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Translational Epigenomic Program, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota; and faubion.william@mayo.edu.
authors.forename: William A
authors.initials: WA
authors.lastname: Faubion
mesh_terms: D000818:Animals; D001665:Binding Sites; D042002:Chromatin Assembly and Disassembly; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D003106:Colon / Q000201:enzymology* / Q000276:immunology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D051765:Early Growth Response Transcription Factors / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D009154:Mutation; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D015398:Signal Transduction; D056264:Sin3 Histone Deacetylase and Corepressor Complex / Q000737:chemistry / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology* / Q000276:immunology; D014162:Transfection; D015854:Up-Regulation; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D016264:Dextran Sulfate; D051765:Early Growth Response Transcription Factors; D051858:Forkhead Transcription Factors; D051741:Kruppel-Like Transcription Factors; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C418974:FOXP3 protein, human; C498833:Foxp3 protein, mouse; C098111:KLF10 protein, human; C569958:KLF10 protein, mouse
keywords: FOXP3; KLF10; PCAF; Sin3; T regulatory cell