Excessive fibrogenesis disrupts normal liver structure,impairs liver function,and precipitates the development of cirrhosis,an irreversible end-stage liver disease.A host of factors including nutrition surplus contrib...Excessive fibrogenesis disrupts normal liver structure,impairs liver function,and precipitates the development of cirrhosis,an irreversible end-stage liver disease.A host of factors including nutrition surplus contribute to liver fibrosis but the underlying mechanism is not fully understood.In the present study,we investigated the involvement of protein inhibitor for activated stat 4（PIAS4）in liver fibrosis in a mouse model of non-alcoholic steatohepatitis（NASH）.We report that PIAS4 silencing using short hairpin RNA（shRNA）attenuated high-fat high-carbohydrate（HFHC）diet induced liver fibrosis in mice.Quantitative PCR and Western blotting analyses confirmed that PIAS4 knockdown downregulated a panel of pro-fibrogenic genes including type I and type III collagens,smooth muscle actin,and tissue inhibitors of metalloproteinase.Mechanistically,PIAS4 silencing blocked the recruitment of SMAD3,a potent pro-fibrogenic transcription factor,to the promoter regions of pro-fibrogenic genes and dampened SMAD3 acetylation likely by upregulating SIRT1 expression.In conclusion,PIAS4 may contribute to liver fibrosis by modulating SIRT1-dependent SMAD3 acetylation.展开更多
Post-translational modifications(PTMs)are dynamic processes that regulate cell states by enhancing proteome diversity.However,the overall impact of PTMs on pluripotency exit in porcine embryonic stem cells(pESCs)remai...Post-translational modifications(PTMs)are dynamic processes that regulate cell states by enhancing proteome diversity.However,the overall impact of PTMs on pluripotency exit in porcine embryonic stem cells(pESCs)remains largely unknown.Here,we present a systematic assay to identify E3 ubiquitin ligases for pluripotency exit by using CRISPR/Cas9 pooled screening and identified PIAS4 as a major regulator of pluripotency exit,as the cell differentiation was significantly impaired upon PIAS4 depletion in pESCs.PIAS4 shows a high degree of genomic occupation in promoter regions,particularly in key pluripotency maintenance genes.Moreover,we found that PIAS4 was recruited to the gene promoter marked by H3K4me3 and interacted with lysine demethylase KDM5B via SUMOylation,thereby affecting the stability of KDM5B and further facilitating the regulation of H3K4me3-mediated lineage-specific genes.Together,our findings reveal a regulatory mechanism by which PIAS4 modulates H3K4me3 modification on development-related genes,subsequently influencing pluripotency exit and cell fate commitment by interacting with KDM5B in pESCs.展开更多
基金supported by the Natural Science Foundation of China(No.81500441)
文摘Excessive fibrogenesis disrupts normal liver structure,impairs liver function,and precipitates the development of cirrhosis,an irreversible end-stage liver disease.A host of factors including nutrition surplus contribute to liver fibrosis but the underlying mechanism is not fully understood.In the present study,we investigated the involvement of protein inhibitor for activated stat 4（PIAS4）in liver fibrosis in a mouse model of non-alcoholic steatohepatitis（NASH）.We report that PIAS4 silencing using short hairpin RNA（shRNA）attenuated high-fat high-carbohydrate（HFHC）diet induced liver fibrosis in mice.Quantitative PCR and Western blotting analyses confirmed that PIAS4 knockdown downregulated a panel of pro-fibrogenic genes including type I and type III collagens,smooth muscle actin,and tissue inhibitors of metalloproteinase.Mechanistically,PIAS4 silencing blocked the recruitment of SMAD3,a potent pro-fibrogenic transcription factor,to the promoter regions of pro-fibrogenic genes and dampened SMAD3 acetylation likely by upregulating SIRT1 expression.In conclusion,PIAS4 may contribute to liver fibrosis by modulating SIRT1-dependent SMAD3 acetylation.
基金supported by the National Key R&D Program of China(2022YFD1302200)Scientific Innovation 2030 Project(2023ZD04072,2023ZD0404703)+2 种基金the Natural Science Foundation of Hubei Province(2022CFB149)the Fundamental Research Funds for the Central Universities(2662023DKPY001)the Special Research Project on Experimental Animal of Hubei Province(2023CFA006).
文摘Post-translational modifications(PTMs)are dynamic processes that regulate cell states by enhancing proteome diversity.However,the overall impact of PTMs on pluripotency exit in porcine embryonic stem cells(pESCs)remains largely unknown.Here,we present a systematic assay to identify E3 ubiquitin ligases for pluripotency exit by using CRISPR/Cas9 pooled screening and identified PIAS4 as a major regulator of pluripotency exit,as the cell differentiation was significantly impaired upon PIAS4 depletion in pESCs.PIAS4 shows a high degree of genomic occupation in promoter regions,particularly in key pluripotency maintenance genes.Moreover,we found that PIAS4 was recruited to the gene promoter marked by H3K4me3 and interacted with lysine demethylase KDM5B via SUMOylation,thereby affecting the stability of KDM5B and further facilitating the regulation of H3K4me3-mediated lineage-specific genes.Together,our findings reveal a regulatory mechanism by which PIAS4 modulates H3K4me3 modification on development-related genes,subsequently influencing pluripotency exit and cell fate commitment by interacting with KDM5B in pESCs.
