Protein citrullination,including histone H1 and H3 citrullination,is important for transcriptional regulation,DNA damage response,and pluripotency of embryonic stem cells(ESCs).Tripartite motif containing 28(Trim28),a...Protein citrullination,including histone H1 and H3 citrullination,is important for transcriptional regulation,DNA damage response,and pluripotency of embryonic stem cells(ESCs).Tripartite motif containing 28(Trim28),an embryonic development regulator involved in ESC self-renewal,has recently been identified as a novel substrate for citrullination by Padi4.However,the physiological functions of Trim28 citrullination and its role in regulating the chromatin structure and gene transcription of ESCs remain unknown.In this paper,we show that Trim28 is specifically citrullinated in mouse ESCs(m ESCs),and that the loss of Trim28 citrullination induces loss of pluripotency.Mechanistically,Trim28 citrullination enhances the interaction of Trim28with Smarcad1 and prevents chromatin condensation.Additionally,Trim28 citrullination regulates m ESC pluripotency by promoting transcription of Nanog and Klf4 which it does by increasing the enrichment of H3K27ac and H3K4me3 and decreasing the enrichment of H3K9me3 in the transcriptional regulatory region.Thus,our findings suggest that Trim28citrullination is the key for the epigenetic activation of pluripotency genes and pluripotency maintenance of ESCs.Together,these results uncover a role Trim28 citrullination plays in pluripotency regulation and provide novel insight into how citrullination of proteins other than histones regulates chromatin compaction.展开更多
Chemoresistance has long been the bottleneck of ovarian cancer(OC)prognosis.It has been shown that mitochondria play a crucial role in cell response to chemotherapy and that dysregulated mitochondrial dynamics is intr...Chemoresistance has long been the bottleneck of ovarian cancer(OC)prognosis.It has been shown that mitochondria play a crucial role in cell response to chemotherapy and that dysregulated mitochondrial dynamics is intricately linked with diseases like OC,but the underlying mechanisms remain equivocal.Here,we demonstrate a new mechanism where CRL4^(CUL4A/DDB1)manipulates OC cell chemoresistance by regulating mitochondrial dynamics and mitophagy.CRL4^(CUL4A/DDB1)depletion enhanced mitochondrial fission by upregulating AMPKα^(Thr172)and MFF^(Ser172/Ser146)phosphorylation,which in turn recruited DRP1 to mitochondria.CRL4^(CUL4A/DDB1)loss stimulated mitophagy through the Parkin-PINK1 pathway to degrade the dysfunctional and fragmented mitochondria.Importantly,CRL4^(CUL4A/DDB1)loss inhibited OC cell proliferation,whereas inhibiting autophagy partially reversed this disruption.Our findings provide novel insight into the multifaceted function of the CRL4 E3 ubiquitin ligase complex in regulating mitochondrial fission,mitophagy,and OC chemoresistance.Disruption of CRL4^(CUL4A/DDB1)and mitophagy may be a promising therapeutic strategy to overcome chemoresistance in OC.展开更多
基金supported by the National Natural Science Foundation of China(31972884)the National Key Research and Development Program of China(2018YFC1312300)+3 种基金the National Clinical Research Center for Geriatrics(Z20201007)1·3·5 Project for Disciplines of Excellence,West China Hospital(ZYGD18003)the Postdoctoral Research Project,West China Hospital,Sichuan University(18HXBH068)the Natural Science Foundation of Sichuan,China(2022NSFSC1424)。
文摘Protein citrullination,including histone H1 and H3 citrullination,is important for transcriptional regulation,DNA damage response,and pluripotency of embryonic stem cells(ESCs).Tripartite motif containing 28(Trim28),an embryonic development regulator involved in ESC self-renewal,has recently been identified as a novel substrate for citrullination by Padi4.However,the physiological functions of Trim28 citrullination and its role in regulating the chromatin structure and gene transcription of ESCs remain unknown.In this paper,we show that Trim28 is specifically citrullinated in mouse ESCs(m ESCs),and that the loss of Trim28 citrullination induces loss of pluripotency.Mechanistically,Trim28 citrullination enhances the interaction of Trim28with Smarcad1 and prevents chromatin condensation.Additionally,Trim28 citrullination regulates m ESC pluripotency by promoting transcription of Nanog and Klf4 which it does by increasing the enrichment of H3K27ac and H3K4me3 and decreasing the enrichment of H3K9me3 in the transcriptional regulatory region.Thus,our findings suggest that Trim28citrullination is the key for the epigenetic activation of pluripotency genes and pluripotency maintenance of ESCs.Together,these results uncover a role Trim28 citrullination plays in pluripotency regulation and provide novel insight into how citrullination of proteins other than histones regulates chromatin compaction.
基金supported by grants from the National Natural Science Foundation of China(81903083 to LQ and 31972884 to JH)the National Key Research and Development Program of China(2018YFC1312300)+1 种基金the National Clinical Research Center for Geriatrics(Z20201007 to JH)1·3·5 Project for Disciplines of Excellence,West China Hospital(ZYGD18003 to J.H.and ZYJC21021 to Z.C.).
文摘Chemoresistance has long been the bottleneck of ovarian cancer(OC)prognosis.It has been shown that mitochondria play a crucial role in cell response to chemotherapy and that dysregulated mitochondrial dynamics is intricately linked with diseases like OC,but the underlying mechanisms remain equivocal.Here,we demonstrate a new mechanism where CRL4^(CUL4A/DDB1)manipulates OC cell chemoresistance by regulating mitochondrial dynamics and mitophagy.CRL4^(CUL4A/DDB1)depletion enhanced mitochondrial fission by upregulating AMPKα^(Thr172)and MFF^(Ser172/Ser146)phosphorylation,which in turn recruited DRP1 to mitochondria.CRL4^(CUL4A/DDB1)loss stimulated mitophagy through the Parkin-PINK1 pathway to degrade the dysfunctional and fragmented mitochondria.Importantly,CRL4^(CUL4A/DDB1)loss inhibited OC cell proliferation,whereas inhibiting autophagy partially reversed this disruption.Our findings provide novel insight into the multifaceted function of the CRL4 E3 ubiquitin ligase complex in regulating mitochondrial fission,mitophagy,and OC chemoresistance.Disruption of CRL4^(CUL4A/DDB1)and mitophagy may be a promising therapeutic strategy to overcome chemoresistance in OC.