title: The type III histone deacetylase Sirt1 protein suppresses p300-mediated histone H3 lysine 56 acetylation at Bclaf1 promoter to inhibit T cell activation.
abstract: The NAD-dependent histone deacetylase Sirt1 is a negative regulator of T cell activation. Here we report that Sirt1 inhibits T cell activation by suppressing the transcription of Bcl2-associated factor 1 (Bclaf1), a protein required for T cell activation. Sirt1-null T cells have increased acetylation of the histone 3 lysine 56 residue (H3K56) at the bclaf1 promoter, as well as increasing Bclaf1 transcription. Sirt1 binds to bclaf1 promoter upon T cell receptor (TCR)/CD28 stimulation by forming a complex with histone acetyltransferase p300 and NF-κB transcription factor Rel-A. The recruitment of Sirt1, but not p300, requires Rel-A because blocking Rel-A nuclear translocation in T cells and siRNA-mediated knockdown of Rel-A can inhibit Sirt1 binding to bclaf1 promoter. Although knockdown of either p300 or GCN5 partially suppressed global H3K56 acetylation, only p300 knockdown specifically attenuated H3K56 acetylation at the bclaf1 promoter. Lastly, knockdown of Bclaf1 suppresses the hyperactivation observed in Sirt1(-/-) T cells, indicated by less IL-2 production in CD4(+) T cells and reduced proliferation. Therefore, Sirt1 negatively regulates T cell activation via H3K56 deacetylation at the promoter region to inhibit transcription of Bclaf1.
authors: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors: Sinyi
authors: S
authors: Kong
authors: Seung-Jae
authors: SJ
authors: Kim
authors: Barry
authors: B
authors: Sandal
authors: Sang-Myeong
authors: SM
authors: Lee
authors: Beixue
authors: B
authors: Gao
authors: Donna D
authors: DD
authors: Zhang
authors: Deyu
authors: D
authors: Fang
mesh_terms: D000107:Acetylation; D000818:Animals; D018106:CD28 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000737:chemistry*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D008239:Lysine / Q000737:chemistry*; D051379:Mice; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology*; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: C539097:Bclaf1 protein, mouse; D018106:CD28 Antigens; D006657:Histones; D007376:Interleukin-2; C498144:Rela protein, mouse; D012097:Repressor Proteins; D051996:Transcription Factor RelA; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D006655:Histone Deacetylases; D008239:Lysine