title: Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage.
abstract: Phenotypic plasticity of T helper 17 (Th17) cells suggests instability of chromatin structure of key genes of this lineage. We identified epigenetic modifications across the clustered Il17a and Il17f and the Ifng loci before and after differential IL-12 or TGF-beta cytokine signaling, which induce divergent fates of Th17 cell precursors. We found that Th17 cell precursors had substantial remodeling of the Ifng locus, but underwent critical additional modifications to enable high expression when stimulated by IL-12. Permissive modifications across the Il17a-Il17f locus were amplified by TGF-beta signaling in Th17 cells, but were rapidly reversed downstream of IL-12-induced silencing of the Rorc gene by the transcription factors STAT4 and T-bet. These findings reveal substantial chromatin instability of key transcription factor and cytokine genes of Th17 cells and support a model of Th17 cell lineage plasticity in which cell-extrinsic factors modulate Th17 cell fates through differential effects on the epigenetic status of Th17 cell lineage factors.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Mukasa
authors.forename: Anand
authors.initials: A
authors.lastname: Balasubramani
authors.forename: Yun Kyung
authors.initials: YK
authors.lastname: Lee
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Whitley
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Weaver
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Shibata
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Crawford
authors.forename: Robin D
authors.initials: RD
authors.lastname: Hatton
authors.forename: Casey T
authors.initials: CT
authors.lastname: Weaver
mesh_terms: D000818:Animals; D019070:Cell Lineage; D002478:Cells, Cultured; D044127:Epigenesis, Genetic; D005434:Flow Cytometry; D020868:Gene Silencing; D056426:Genetic Loci; D042822:Genomic Instability; D015151:Immunoblotting; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics; D000098815:T-bet Transcription Factor
chemical_list: D020381:Interleukin-17; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors
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