Dysregulation of gut homeostasis is associated with irritable bowel syndrome(IBS),a chronic functional gastrointestinal disorder affecting approximately 11.2%of the global population.The poorly understood pathogenesis...Dysregulation of gut homeostasis is associated with irritable bowel syndrome(IBS),a chronic functional gastrointestinal disorder affecting approximately 11.2%of the global population.The poorly understood pathogenesis of IBS has impeded its treatment.Here,we report that the E3 ubiquitin ligase tripartite motif-containing 27(TRIM27)is weakly expressed in IBS but highly expressed in inflammatory bowel disease(IBD),a frequent chronic organic gastrointestinal disorder.Accordingly,knockout of Trim27 in mice causes spontaneously occurring IBS-like symptoms,including increased visceral hyperalgesia and abnormal stool features,as observed in IBS patients.Mechanistically,TRIM27 stabilizesβ-catenin and thus activates Wnt/β-catenin signaling to promote intestinal stem cell(ISC)self-renewal.Consistent with these findings,Trim27 deficiency disrupts organoid formation,which is rescued by reintroducing TRIM27 orβ-catenin.Furthermore,Wnt/β-catenin signaling activator treatment ameliorates IBS symptoms by promoting ISC self-renewal.Taken together,these data indicate that TRIM27 is critical for maintaining gut homeostasis,suggesting that targeting the TRIM27/Wnt/β-catenin axis could be a potential treatment strategy for IBS.Our study also indicates that TRIM27 might serve as a potential biomarker for differentiating IBS from IBD.展开更多
Viral myocarditis(VM) is an inflammatory disease of the myocardium associated with heart failure, which is caused by common viral infections. A majority of the infections are initiated by coxsackievirus B3(CVB3). Micr...Viral myocarditis(VM) is an inflammatory disease of the myocardium associated with heart failure, which is caused by common viral infections. A majority of the infections are initiated by coxsackievirus B3(CVB3). Micro RNAs(mi RNAs)have a major role in various biological processes, including gene expression, cell growth, proliferation, and apoptosis, as well as viral infection and antiviral immune responses. Although, mi RNAs have been found to regulate viral infections,their role in CVB3 infection remains poorly understood. In the previous study, mi RNA microarray results showed that mi R-324-3 p expression levels were significantly increased when cells and mice were infected with CVB3. It was also found that miR-324-3p downregulated TRIM27 and decreased CVB3 replication in vitro and in vivo. In vitro, analysis of downstream signaling of TRIM27 revealed that, miR-324-3p inhibited CVB3 infection, and reduced cytopathic effect and viral plaque formation by reducing the expression of TRIM27. In vivo, miR-324-3p decreased the expression of TRIM27,reduced cardiac viral replication and load, thereby strongly attenuating cardiac injury and inflammation. Taken together,this study suggests that miR-324-3p targets TRIM27 to inhibit CVB3 replication and viral load, thereby reducing the cardiac injury associated with VM.展开更多
Histone methylation is a context-dependent modification that regulates gene expression,and the trimethylation of histone H3 lysine 27(H3K27me3)usually induces gene silencing.Overcoming colorectal cancer(CRC)chemoresis...Histone methylation is a context-dependent modification that regulates gene expression,and the trimethylation of histone H3 lysine 27(H3K27me3)usually induces gene silencing.Overcoming colorectal cancer(CRC)chemoresistance is currently a huge challenge,but the relationship between H3K27me3 modification and chemoresistance remains largely unclear.Here,we found that H3K27me3 levels positively correlated with the metastasis-free survival of CRC patients and a low H3K27me3 level predicted a poor outcome upon chemotherapeutic drug treatment.Oxaliplatin stimulation significantly induced the expression of H3K27 lysine demethylase 6A/6B(KDM6A/6B),thus decreasing the level of H3K27me3 in CRC cells.Elevation of H3K27me3 level through KDM6A/6B depletion or GSK-J4(a KDM6A/6B inhibitor)treatment significantly enhanced oxaliplatin-induced apoptosis.Conversely,when inhibiting the expression of H3K27me3 by EPZ-6438,an inhibitor of the histone methyltransferase EZH2,the proportion of apoptotic cells remarkably decreased.In addition,the combination of GSK-J4 and oxaliplatin significantly inhibited tumor growth in an oxaliplatin-resistant patient-derived xenograft model.Importantly,we revealed that oxaliplatin treatment dramatically induced NOTCH2 expression,which was caused by downregulation of H3K27me3 level on the NOTCH2 transcription initiation site.Thus,the activated NOTCH signaling promoted the expression of stemness-related genes,which resulted in oxaliplatin resistance.Furthermore,oxaliplatin-induced NOTCH signaling could be interrupted by GSK-J4 treatment.Collectively,our findings suggest that elevating H3K27me3 level can improve drug sensitivity in CRC patients.展开更多
基金supported by the National Key Research and Development Project of China(2021YFA1300200 to CHL and LZ,2022YFC2302900 to CHL and JW)the National Natural Science Foundation of China(81825014 to CHL,31830003 to CHL,82022041 to JW and 81871616 to JW)+2 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29020000 to CHL)Youth Innovation Promotion Association CAS(2018118 to JW)the State Key Laboratory of Proteomics(SKLP-K202001 to LZ and SKLPO202003 to JW).
文摘Dysregulation of gut homeostasis is associated with irritable bowel syndrome(IBS),a chronic functional gastrointestinal disorder affecting approximately 11.2%of the global population.The poorly understood pathogenesis of IBS has impeded its treatment.Here,we report that the E3 ubiquitin ligase tripartite motif-containing 27(TRIM27)is weakly expressed in IBS but highly expressed in inflammatory bowel disease(IBD),a frequent chronic organic gastrointestinal disorder.Accordingly,knockout of Trim27 in mice causes spontaneously occurring IBS-like symptoms,including increased visceral hyperalgesia and abnormal stool features,as observed in IBS patients.Mechanistically,TRIM27 stabilizesβ-catenin and thus activates Wnt/β-catenin signaling to promote intestinal stem cell(ISC)self-renewal.Consistent with these findings,Trim27 deficiency disrupts organoid formation,which is rescued by reintroducing TRIM27 orβ-catenin.Furthermore,Wnt/β-catenin signaling activator treatment ameliorates IBS symptoms by promoting ISC self-renewal.Taken together,these data indicate that TRIM27 is critical for maintaining gut homeostasis,suggesting that targeting the TRIM27/Wnt/β-catenin axis could be a potential treatment strategy for IBS.Our study also indicates that TRIM27 might serve as a potential biomarker for differentiating IBS from IBD.
基金The research was support by National Natural Science Foundation of China,Grant No.81971945 and No.81802013(https://isisn.nsfc.gov.cn/egrantweb/)Xuzhou Science and Technology Project,Grant No.KC1717(http://kjj.xz.gov.cn)the Projects from Social development of Zhenjiang,Grant No.SH2019044(http://kjj.zhenjiang.gov.cn)。
文摘Viral myocarditis(VM) is an inflammatory disease of the myocardium associated with heart failure, which is caused by common viral infections. A majority of the infections are initiated by coxsackievirus B3(CVB3). Micro RNAs(mi RNAs)have a major role in various biological processes, including gene expression, cell growth, proliferation, and apoptosis, as well as viral infection and antiviral immune responses. Although, mi RNAs have been found to regulate viral infections,their role in CVB3 infection remains poorly understood. In the previous study, mi RNA microarray results showed that mi R-324-3 p expression levels were significantly increased when cells and mice were infected with CVB3. It was also found that miR-324-3p downregulated TRIM27 and decreased CVB3 replication in vitro and in vivo. In vitro, analysis of downstream signaling of TRIM27 revealed that, miR-324-3p inhibited CVB3 infection, and reduced cytopathic effect and viral plaque formation by reducing the expression of TRIM27. In vivo, miR-324-3p decreased the expression of TRIM27,reduced cardiac viral replication and load, thereby strongly attenuating cardiac injury and inflammation. Taken together,this study suggests that miR-324-3p targets TRIM27 to inhibit CVB3 replication and viral load, thereby reducing the cardiac injury associated with VM.
基金This work was supported by the National Program on Key Research(2018YFA0107500 and 2016YFC1302400)the National Natural Science Foundation of China(91742113 and 31570902)Natural Science Foundation of Shanghai(14ZR14-26300,18ZR1424400,18ZR1446400,and 18431902700).
文摘Histone methylation is a context-dependent modification that regulates gene expression,and the trimethylation of histone H3 lysine 27(H3K27me3)usually induces gene silencing.Overcoming colorectal cancer(CRC)chemoresistance is currently a huge challenge,but the relationship between H3K27me3 modification and chemoresistance remains largely unclear.Here,we found that H3K27me3 levels positively correlated with the metastasis-free survival of CRC patients and a low H3K27me3 level predicted a poor outcome upon chemotherapeutic drug treatment.Oxaliplatin stimulation significantly induced the expression of H3K27 lysine demethylase 6A/6B(KDM6A/6B),thus decreasing the level of H3K27me3 in CRC cells.Elevation of H3K27me3 level through KDM6A/6B depletion or GSK-J4(a KDM6A/6B inhibitor)treatment significantly enhanced oxaliplatin-induced apoptosis.Conversely,when inhibiting the expression of H3K27me3 by EPZ-6438,an inhibitor of the histone methyltransferase EZH2,the proportion of apoptotic cells remarkably decreased.In addition,the combination of GSK-J4 and oxaliplatin significantly inhibited tumor growth in an oxaliplatin-resistant patient-derived xenograft model.Importantly,we revealed that oxaliplatin treatment dramatically induced NOTCH2 expression,which was caused by downregulation of H3K27me3 level on the NOTCH2 transcription initiation site.Thus,the activated NOTCH signaling promoted the expression of stemness-related genes,which resulted in oxaliplatin resistance.Furthermore,oxaliplatin-induced NOTCH signaling could be interrupted by GSK-J4 treatment.Collectively,our findings suggest that elevating H3K27me3 level can improve drug sensitivity in CRC patients.
