title: The Regulatory T Cell Lineage Factor Foxp3 Regulates Gene Expression through Several Distinct Mechanisms Mostly Independent of Direct DNA Binding.
abstract: The lineage factor Foxp3 is essential for the development and maintenance of regulatory T cells, but little is known about the mechanisms involved. Here, we demonstrate that an N-terminal proline-rich interaction region is crucial for Foxp3's function. Subdomains within this key region link Foxp3 to several independent mechanisms of transcriptional regulation. Our study suggests that Foxp3, even in the absence of its DNA-binding forkhead domain, acts as a bridge between DNA-binding interaction partners and proteins with effector function permitting it to regulate a large number of genes. We show that, in one such mechanism, Foxp3 recruits class I histone deacetylases to the promoters of target genes, counteracting activation-induced histone acetylation and thereby suppressing their expression.
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.
authors.forename: Xin
authors.initials: X
authors.lastname: Xie
authors.affiliation: European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom.
authors.forename: Michael J T
authors.initials: MJ
authors.lastname: Stubbington
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.
authors.forename: Jesper K
authors.initials: JK
authors.lastname: Nissen
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.
authors.forename: Kristian G
authors.initials: KG
authors.lastname: Andersen
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hebenstreit
authors.affiliation: European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Hinxton, United Kingdom.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Teichmann
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Betz
mesh_terms: D000818:Animals; D019070:Cell Lineage; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D008807:Mice, Inbred BALB C; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000502:physiology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006657:Histones; D007376:Interleukin-2; D004247:DNA; D006655:Histone Deacetylases