TY - JOUR
T1 - Guidance of super-enhancers in regulation of IL-9 induction and airway inflammation
AU - Xiao, Xiang
AU - Fan, Yihui
AU - Li, Junhui
AU - Zhang, Xiaolong
AU - Lou, Xiaohua
AU - Dou, Yaling
AU - Shi, Xiaomin
AU - Lan, Peixiang
AU - Xiao, Yue
AU - Minze, Laurie
AU - Li, Xian Chang
N1 - Funding Information:
We thank Professor Naoto Ishii at Tohoku University (Sendai, Japan) for the generous gift of OX40Ltg mice. We also acknowledge the excellent services from the flow cytometry core and the pathology core at Houston Methodist Hospital in Houston, TX. This work was supported by grants from the National Institutes of Health (R01AI129906 and R01AI106200). The authors declare no competing financial interests
Funding Information:
This work was supported by grants from the National Institutes of Health (R01AI129906 and R01AI106200). The authors declare no competing financial interests.
Publisher Copyright:
© 2018 Xiao et al.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - Th9 cells are prominently featured in allergic lung inflammation, but the mechanism that regulates IL-9 induction in T helper cells remains poorly defined. Here we demonstrate that formation of super-enhancers (SEs) is critical in robust induction of IL-9 and that assembly of the Il9 SEs in Th cells requires OX40-triggered chromatin acetylation. Mechanistically, we found that OX40 costimulation induces RelB expression, which recruits the histone acetyltransferase p300 to the Il9 locus to catalyze H3K27 acetylation. This allows binding of the SE factor Brd4 to organize assembly of the SE complex, which in turn drives robust IL-9 expression and Th9 cell induction. Thus, Th9 cells are strongly induced upon OX40 stimulation, and disruption of SEs abolished Th9 cell induction in vitro and inhibited Th9 cell-mediated allergic airway inflammation in vivo. Together, our data suggest that formation of SEs is essential in IL-9 expression and Th9 cell induction. These findings may have important clinical implications.
AB - Th9 cells are prominently featured in allergic lung inflammation, but the mechanism that regulates IL-9 induction in T helper cells remains poorly defined. Here we demonstrate that formation of super-enhancers (SEs) is critical in robust induction of IL-9 and that assembly of the Il9 SEs in Th cells requires OX40-triggered chromatin acetylation. Mechanistically, we found that OX40 costimulation induces RelB expression, which recruits the histone acetyltransferase p300 to the Il9 locus to catalyze H3K27 acetylation. This allows binding of the SE factor Brd4 to organize assembly of the SE complex, which in turn drives robust IL-9 expression and Th9 cell induction. Thus, Th9 cells are strongly induced upon OX40 stimulation, and disruption of SEs abolished Th9 cell induction in vitro and inhibited Th9 cell-mediated allergic airway inflammation in vivo. Together, our data suggest that formation of SEs is essential in IL-9 expression and Th9 cell induction. These findings may have important clinical implications.
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U2 - 10.1084/jem.20170928
DO - 10.1084/jem.20170928
M3 - Article
C2 - 29339447
AN - SCOPUS:85041420453
VL - 215
SP - 559
EP - 574
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 2
ER -