title: T-bet dependent removal of Sin3A-histone deacetylase complexes at the Ifng locus drives Th1 differentiation.
abstract: Forming and removing epigenetic histone marks at gene loci are central processes in differentiation. Here, we explored mechanisms establishing long-range H4 acetylation marks at the Ifng locus during Th1 lineage commitment. In Th0 cells, histone deacetylase (HDAC)-Sin3A complexes recruited to the Ifng locus actively prevented accumulation of H4 acetylation marks. Th1 differentiation caused loss of HDAC-Sin3A complexes by T-bet-dependent mechanisms and accumulation of H4 acetylation marks. HDAC-Sin3A complexes were absent from the locus in NOD Th0 cells, obviating the need for Th1 differentiation signals to establish histone marks and Th1 differentiation. Thus, Ifng transcription is actively prevented in Th0 cells via epigenetic mechanisms and epigenetic defects allow unregulated Ifng transcription that may contribute to autoimmunity.
authors.affiliation: Department of Medicine, Division of Rheumatology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Shaojing
authors.initials: S
authors.lastname: Chang
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Collins
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Aune
mesh_terms: D000107:Acetylation; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D051548:Histone Acetyltransferases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D021381:Protein Transport / Q000276:immunology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D020825:T-Box Domain Proteins / Q000502:physiology*; D018417:Th1 Cells / Q000166:cytology* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D000098815:T-bet Transcription Factor
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex