The transcriptional repressor Hes1 attenuates inflammation by regulating transcription elongation

The chemokine CXCL1 serves a critical role in inflammation by mediating the recruitment of neutrophils. Hu and colleagues demonstrate that the transcriptional repressor Hes1 controls CXCL1 via an unusual mechanism that prevents 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.