Mechanisms by which LPCs perform hepatocyte functions and differentiate into hepatocytes. (IMAGE)
Caption
(A) Following MHN, the expression of coagulation factors in LPCs is activated by activin. Activin signalling in LPCs is negatively regulated by follistatin, a hormone controlled by insulin and glucagon. (B) A hepatic hierarchical transcription network regulates the transcription of ALB and CPS1. Under physiological conditions, hepatocytes use the pioneer factor FOXA2 to support the master transcription factors HNF4α and C/EBPα in regulating the transcription of these two genes. In cases of severe liver injury, both HNF4α and C/EBPα are inhibited by inflammatory cytokines such as TGF-β. FOXA2 then coordinates with the alternative transcription factor RAR to maintain ALB and CPS1 transcription in hepatocytes. When the liver suffers from MHN, activated LPCs express the three key transcription factors—FOXA2, HNF4α and C/EBPα—to initiate the transcription of ALB and CPS1. (C) Liver function genes are associated with super-enhancers in hepatocytes, but not in LPCs. During the differentiation of LPCs into hepatocytes, LPCs form super-enhancers on liver function genes, supported by FOXAs. Created with BioRender.com. ALB, albumin; BRD4, bromodomain-containing protein 4; BRG1, brahma-related gene 1; C/EBP, CCAAT/enhancer binding protein; CPS1, carbamoyl phosphate synthetase I; CTCF, CCCTC-binding factor; FOXA, forkhead box A; FOXH1, forkhead box H1; HC, hepatocyte; HNF4α, hepatocyte nuclear factor 4α; LPC, liver progenitor cell; MED1, mediator complex subunit 1; MHN, massive hepatic necrosis; RA, retinoic acid; RAR, retinoic acid receptor; SE, super-enhancer; SMAD, SMA and MAD-related protein; TGF-β, transforming growth factor-β; TSS, transcription start site.
Credit
By Honglei Weng, Roman Liebe, et al.
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CC BY