Identification of a distal enhancer that determines the expression pattern of acute phase marker C-reactive protein

C-reactive protein (CRP) is a major acute phase protein and inflammatory marker, the expression of which is largely liver specific and highly inducible. Enhancers are regulatory elements critical for the precise activation of gene expression, yet the contributions of enhancers to the expression patt...

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Veröffentlicht in:The Journal of biological chemistry 2022-08, Vol.298 (8), p.102160-102160, Article 102160
Hauptverfasser: Wang, Ming-Yu, Zhang, Chun-Miao, Zhou, Hai-Hong, Ge, Zhong-Bo, Su, Chen-Chen, Lou, Zi-Hao, Zhang, Xin-Yun, Xu, Tao-Tao, Li, Si-Yi, Zhu, Li, Zhou, Ya-Li, Wu, Yi, Ji, Shang-Rong
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container_end_page 102160
container_issue 8
container_start_page 102160
container_title The Journal of biological chemistry
container_volume 298
creator Wang, Ming-Yu
Zhang, Chun-Miao
Zhou, Hai-Hong
Ge, Zhong-Bo
Su, Chen-Chen
Lou, Zi-Hao
Zhang, Xin-Yun
Xu, Tao-Tao
Li, Si-Yi
Zhu, Li
Zhou, Ya-Li
Wu, Yi
Ji, Shang-Rong
description C-reactive protein (CRP) is a major acute phase protein and inflammatory marker, the expression of which is largely liver specific and highly inducible. Enhancers are regulatory elements critical for the precise activation of gene expression, yet the contributions of enhancers to the expression pattern of CRP have not been well defined. Here, we identify a constitutively active enhancer (E1) located 37.7 kb upstream of the promoter of human CRP in hepatocytes. By using chromatin immunoprecipitation, luciferase reporter assay, in situ genetic manipulation, CRISPRi, and CRISPRa, we show that E1 is enriched in binding sites for transcription factors STAT3 and C/EBP-β and is essential for the full induction of human CRP during the acute phase. Moreover, we demonstrate that E1 orchestrates with the promoter of CRP to determine its varied expression across tissues and species through surveying activities of E1-promoter hybrids and the associated epigenetic modifications. These results thus suggest an intriguing mode of molecular evolution wherein expression-changing mutations in distal regulatory elements initiate subsequent functional selection involving coupling among distal/proximal regulatory mutations and activity-changing coding mutations.
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subjects acute phase response
C-reactive protein
enhancer
evolution
inflammation
STAT3
title Identification of a distal enhancer that determines the expression pattern of acute phase marker C-reactive protein
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