title: FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression.
abstract: The forkhead family protein FOXP3 acts as a repressor of transcription and is both an essential and sufficient regulator of the development and function of regulatory T cells. The molecular mechanism by which FOXP3-mediated transcriptional repression occurs remains unclear. Here, we report that transcriptional repression by FOXP3 involves a histone acetyltransferase-deacetylase complex that includes histone acetyltransferase TIP60 (Tat-interactive protein, 60 kDa) and class II histone deacetylases HDAC7 and HDAC9. The N-terminal 106-190 aa of FOXP3 are required for TIP60-FOXP3, HDAC7-FOXP3 association, as well as for the transcriptional repression of FOXP3 via its forkhead domain. FOXP3 can be acetylated in primary human regulatory T cells, and TIP60 promotes FOXP3 acetylation in vivo. Overexpression of TIP60 but not its histone acetyltransferase-deficient mutant promotes, whereas knockdown of endogenous TIP60 relieved, FOXP3-mediated transcriptional repression. A minimum FOXP3 ensemble containing native TIP60 and HDAC7 is necessary for IL-2 production regulation in T cells. Moreover, FOXP3 association with HDAC9 is antagonized by T cell stimulation and can be restored by the protein deacetylation inhibitor trichostatin A, indicating a complex dynamic aspect of T suppressor cell regulation. These findings identify a previously uncharacterized complex-based mechanism by which FOXP3 actively mediates transcriptional repression.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, 36th and Hamilton Walk, Philadelphia, PA 19104-6082, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.forename: Arabinda
authors.initials: A
authors.lastname: Samanta
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Song
authors.forename: Kathryn T
authors.initials: KT
authors.lastname: Iacono
authors.forename: Kathryn
authors.initials: K
authors.lastname: Bembas
authors.forename: Ran
authors.initials: R
authors.lastname: Tao
authors.forename: Samik
authors.initials: S
authors.lastname: Basu
authors.forename: James L
authors.initials: JL
authors.lastname: Riley
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
authors.forename: Yuan
authors.initials: Y
authors.lastname: Shen
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Saouaf
authors.forename: Mark I
authors.initials: MI
authors.lastname: Greene
mesh_terms: D015704:CD4 Antigens / Q000096:biosynthesis; D002467:Cell Nucleus / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D000074443:Lysine Acetyltransferase 5; D008954:Models, Biological; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006877:Hydroxamic Acids; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D012097:Repressor Proteins; C012589:trichostatin A; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; C543273:HDAC7 protein, human; C486544:HDAC9 protein, human; D006655:Histone Deacetylases