Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage.
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.
Mukasa
Ryuta
R
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Balasubramani
Anand
A
Lee
Yun Kyung
YK
Whitley
Sarah K
SK
Weaver
Benjamin T
BT
Shibata
Yoichiro
Y
Crawford
Gregory E
GE
Hatton
Robin D
RD
Weaver
Casey T
CT
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
D020381:Interleukin-17; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors
Immunity. 2009 Oct 16;31(4):551-64
19818655
Methods Mol Biol. 2009;556:177-90
19488879
Nat Immunol. 2007 Sep;8(9):931-41
17694059
Nature. 2008 May 1;453(7191):106-9
18362914
J Clin Invest. 2009 Mar;119(3):565-72
19188681
J Biol Chem. 2007 Mar 2;282(9):5969-72
17218320
Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17095-100
16286661
Proc Natl Acad Sci U S A. 2009 Jan 13;106(2):552-7
19122139
Nature. 2009 Jul 16;460(7253):410-3
19458616
Cell. 2007 Feb 23;128(4):693-705
17320507
Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W273-9
15215394
J Immunol Methods. 2005 Aug;303(1-2):105-21
16048727
Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12622-7
15304658
Nat Genet. 2008 Jul;40(7):897-903
18552846
Immunity. 2006 Nov;25(5):717-29
17070076
Nat Immunol. 2008 Nov;9(11):1297-306
18849990
Blood. 2003 Jun 1;101(11):4342-6
12560221
Nat Immunol. 2003 Jul;4(7):616-23
12830136
Proc Natl Acad Sci U S A. 2006 May 23;103(21):8137-42
16698929
Nature. 2008 May 1;453(7191):65-71
18362915
Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20846-51
19088203
Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9721-6
18607004
Immunity. 2009 Jan 16;30(1):92-107
19119024
Eur J Immunol. 2009 Jan;39(1):216-24
19130584
J Immunol. 2008 Nov 15;181(10):7205-13
18981142
Annu Rev Immunol. 2006;24:607-56
16551261
Immunity. 2009 Jan 16;30(1):155-67
19144320
Eur J Immunol. 2008 Oct;38(10):2654-64
18825747
Immunity. 2008 Jan;28(1):29-39
18164222
Nat Methods. 2006 Jul;3(7):503-9
16791207
Cell. 2007 Feb 23;128(4):735-45
17320510
J Biol Chem. 2004 Feb 6;279(6):4802-10
14607827
Nat Rev Immunol. 2009 Feb;9(2):91-105
19151746
Nature. 2009 Jul 16;460(7253):405-9
19578362
Nat Immunol. 2007 Jul;8(7):732-42
17546033
Immunol Rev. 2003 Oct;195:81-90
12969312
Nat Immunol. 2005 Nov;6(11):1123-32
16200070
Cell. 2006 Sep 22;126(6):1121-33
16990136