FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression.
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.
Li
Bin
B
Department of Pathology and Laboratory Medicine, University of Pennsylvania, 36th and Hamilton Walk, Philadelphia, PA 19104-6082, USA.
Samanta
Arabinda
A
Song
Xiaomin
X
Iacono
Kathryn T
KT
Bembas
Kathryn
K
Tao
Ran
R
Basu
Samik
S
Riley
James L
JL
Hancock
Wayne W
WW
Shen
Yuan
Y
Saouaf
Sandra J
SJ
Greene
Mark I
MI
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
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