Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation.
Signal transducer and activator of transcription 4 (STAT4) and STAT6 are key factors in the specification of helper T cells; however, their direct roles in driving differentiation are not well understood. Using chromatin immunoprecipitation and massive parallel sequencing, we quantitated the full complement of STAT-bound genes, concurrently assessing global STAT-dependent epigenetic modifications and gene transcription by using cells from cognate STAT-deficient mice. STAT4 and STAT6 each bound over 4000 genes with distinct binding motifs. Both played critical roles in maintaining chromatin configuration and transcription of a core subset of genes through the combination of different epigenetic patterns. Globally, STAT4 had a more dominant role in promoting active epigenetic marks, whereas STAT6 had a more prominent role in antagonizing repressive marks. Clusters of genes negatively regulated by STATs were also identified, highlighting previously unappreciated repressive roles of STATs. Therefore, STAT4 and STAT6 play wide regulatory roles in T helper cell specification.
Wei
Lai
L
Molecular Immunology and Inflammation Branch, NIAMS, National Institutes of Health, Bethesda MD 20892, USA.
Vahedi
Golnaz
G
Sun
Hong-Wei
HW
Watford
Wendy T
WT
Takatori
Hiroaki
H
Ramos
Haydee L
HL
Takahashi
Hayato
H
Liang
Jonathan
J
Gutierrez-Cruz
Gustavo
G
Zang
Chongzhi
C
Peng
Weiqun
W
O'Shea
John J
JJ
Kanno
Yuka
Y
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000276:immunology*; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic
D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor