The transcriptional repressor Hes1 attenuates inflammation by regulating transcription elongation.
Most of the known regulatory mechanisms that curb inflammatory gene expression target pre-transcription-initiation steps, and evidence for post-initiation regulation of inflammatory gene expression remains scarce. We found that the transcriptional repressor Hes1 suppressed production of CXCL1, a chemokine that is crucial for recruiting neutrophils. Hes1 negatively regulated neutrophil recruitment in vivo in a manner that was dependent on macrophage-produced CXCL1, and it attenuated the severity of inflammatory arthritis. Mechanistically, inhibition of Cxcl1 expression by Hes1 did not involve modification of transcription initiation. Instead, Hes1 inhibited signal-induced recruitment of the positive transcription-elongation complex P-TEFb and thereby prevented phosphorylation of RNA polymerase II at Ser2 and productive elongation. Thus, our results identify Hes1 as a homeostatic suppressor of inflammatory responses that exerts its suppressive function by regulating transcription elongation.
Institute for Immunology and School of Medicine, Tsinghua University, Beijing. China.
Yingli
Y
Shang
Hospital for Special Surgery Research Division and the David Z. Rosensweig Genomics Center, New York, New York, USA.
Maddalena
M
Coppo
Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
Teng
T
He
Institute for Immunology and School of Medicine, Tsinghua University, Beijing. China.
Fei
F
Ning
Institute for Immunology and School of Medicine, Tsinghua University, Beijing. China.
Li
L
Yu
Institute for Immunology and School of Medicine, Tsinghua University, Beijing. China.
Lan
L
Kang
Institute for Immunology and School of Medicine, Tsinghua University, Beijing. China.
Bin
B
Zhang
Hospital for Special Surgery Research Division and the David Z. Rosensweig Genomics Center, New York, New York, USA.
Chanyang
0000-0002-1213-1601
C
Ju
Hospital for Special Surgery Research Division and the David Z. Rosensweig Genomics Center, New York, New York, USA.
Yu
Y
Qiao
Hospital for Special Surgery Research Division and the David Z. Rosensweig Genomics Center, New York, New York, USA.|Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
Baohong
B
Zhao
Developmental Biochemistry, Theodor-Boveri-Institute/Biocenter, and Comprehensive Cancer Center Mainfranken, Wuerzburg University, Wuerzburg, Germany.
Manfred
M
Gessler
Hospital for Special Surgery Research Division and the David Z. Rosensweig Genomics Center, New York, New York, USA.|Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, USA.
Inez
I
Rogatsky
Institute for Immunology and School of Medicine, Tsinghua University, Beijing. China.|Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing, China.
Xiaoyu
0000-0002-4289-6998
X
Hu
D000818:Animals; D001168:Arthritis / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D007249:Inflammation / Q000235:genetics*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D020556:Neutrophil Infiltration / Q000235:genetics; D042925:Positive Transcriptional Elongation Factor B / Q000235:genetics / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism; D061805:Transcription Elongation, Genetic; D000072056:Transcription Factor HES-1 / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; C489734:Hes1 protein, mouse; C120420:Hey1 protein, mouse; D000072056:Transcription Factor HES-1; D042925:Positive Transcriptional Elongation Factor B; D012319:RNA Polymerase II