Genome-wide association studies(GWASs)have identified over 140 colorectal cancer(CRC)-associated loci;however,target genes at the majority of loci and underlying molecular mechanisms are poorly understood.Here,we util...Genome-wide association studies(GWASs)have identified over 140 colorectal cancer(CRC)-associated loci;however,target genes at the majority of loci and underlying molecular mechanisms are poorly understood.Here,we utilized a Bayesian approach,integrative risk gene selector(iRIGS),to prioritize risk genes at CRC GWAS loci by integrating multi-omics data.As a result,a total of 105 high-confidence risk genes(HRGs)were identified,which exhibited strong gene dependencies for CRC and enrichment in the biological processes implicated in CRC.Among the 105 HRGs,CEBPB,located at the 20q13.13 locus,acted as a transcription factor playing critical roles in cancer.Our subsequent assays indicated the tumor promoter function of CEBPB that facilitated CRC cell proliferation by regulating multiple oncogenic pathways such as MAPK,PI3K-Akt,and Ras signaling.Next,by integrating a fine-mapping analysis and three independent case-control studies in Chinese populations consisting of 8,039 cases and 12,775 controls,we elucidated that rs1810503,a putative functional variant regulating CEBPB,was associated with CRC risk(OR=0.90,95%CI=0.86–0.93,P=1.07×10^(−7)).The association between rs1810503 and CRC risk was further validated in three additional multi-ancestry populations consisting of 24,254 cases and 58,741 controls.Mechanistically,the rs1810503 A to T allele change weakened the enhancer activity in an allele-specific manner to decrease CEBPB expression via longrange promoter-enhancer interactions,mediated by the transcription factor,REST,and thus decreased CRC risk.In summary,our study provides a genetic resource and a generalizable strategy for CRC etiology investigation,and highlights the biological implications of CEBPB in CRC tumorigenesis,shedding new light on the etiology of CRC.展开更多
Background Goose, descendants of migratory ancestors, have undergone extensive selective breeding, resulting in their remarkable ability to accumulate fat in the liver and exhibit a high tolerance for significant ener...Background Goose, descendants of migratory ancestors, have undergone extensive selective breeding, resulting in their remarkable ability to accumulate fat in the liver and exhibit a high tolerance for significant energy intake. As a result, goose offers an excellent model for studying obesity, metabolic disorders, and liver diseases in mammals. Although the impact of the three-dimensional arrangement of chromatin within the cell nucleus on gene expression and transcriptional regulation is widely acknowledged, the precise functions of chromatin architecture reorganization during fat deposition in goose liver tissues still need to be fully comprehended.Results In this study, geese exhibited more pronounced changes in the liver index and triglyceride(TG) content following the consumption of the high-fat diet(HFD) than mice without significant signs of inflammation. Additionally, we performed comprehensive analyses on 10 goose liver tissues(5 HFD, 5 normal), including generating highresolution maps of chromatin architecture, conducting whole-genome gene expression profiling, and identifying H3K27ac peaks in the livers of geese and mice subjected to the HFD. Our results unveiled a multiscale restructuring of chromatin architecture, encompassing Compartment A/B, topologically associated domains, and interactions between promoters and enhancers. The dynamism of the three-dimensional genome architecture, prompted by the HFD, assumed a pivotal role in the transcriptional regulation of crucial genes. Furthermore, we identified genes that regulate chromatin conformation changes, contributing to the metabolic adaptation process of lipid deposition and hepatic fat changes in geese in response to excessive energy intake. Moreover, we conducted a cross-species analysis comparing geese and mice exposed to the HFD, revealing unique characteristics specific to the goose liver compared to a mouse. These chromatin conformation changes help elucidate the observed characteristics of fat deposition and hepatic fat regulation in geese u展开更多
目的 构建前列腺特异性膜抗原启动子增强子靶向性调控的 U PRT基因真核表达重组质粒 (p PS-MAenhancer/ promoter- U PRT)。方法 采用 PCR技术从大肠杆菌 JM10 9基因组中扩增 U PRT基因 ,通过分子克隆技术将其克隆到包括前列腺特异性...目的 构建前列腺特异性膜抗原启动子增强子靶向性调控的 U PRT基因真核表达重组质粒 (p PS-MAenhancer/ promoter- U PRT)。方法 采用 PCR技术从大肠杆菌 JM10 9基因组中扩增 U PRT基因 ,通过分子克隆技术将其克隆到包括前列腺特异性膜抗原启动子增强子靶向性调控的 p EGFP- 1的质粒。利用重组质粒 p PS-MAenhancer/ promoter- U PRT)转染 L Ncap细胞 ,MTT法检测 5 -氯尿嘧啶 (5 - FU)对转染 L Ncap细胞存活率的影响。结果 质粒 p PSMAenhancer/ promoter- EGFP双酶切去除 EGFP,连接上 U PRT基因 ,成功构建 p PSMAenhancer/ promoter- UPRT,并转染 L Ncap细胞 ,使 L Ncap细胞对 5 - FU的杀伤敏感性大大提高。结论 p PSMAenhancer/ promoter- U PRT的构建和表达 ,为进一步研究 UPRT基因对 5 - FU的靶向性杀伤前列腺癌细胞增强作用和对前列腺癌自杀基因系统 (CD/ 5 -FC系统 )的放大效应奠定了基础。展开更多
基金This work was supported by the National Natural Science Foundation of China(82103929,82273713)Young Elite Scientists Sponsorship Program by CAST(2022QNRC001)+7 种基金Fundamental Research Funds for the Central Universities(WHU:2042022kf1205)Knowledge Innovation Program of Wuhan(whkxjsj011)Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University(ZNJC202207)for Jianbo TianDistinguished Young Scholars of China(81925032)Key Program of National Natural Science Foundation of China(82130098)the Leading Talent Program of the Health Commission of Hubei Province,Natural Science Foundation of Hubei Province(2019CFA009)the Fundamental Research Funds for the Central Universities(2042022rc0026,2042023kf1005)for Xiaoping Miaothe National Natural Science Foundation of China(82204128)for Xiaoyang Wang.
文摘Genome-wide association studies(GWASs)have identified over 140 colorectal cancer(CRC)-associated loci;however,target genes at the majority of loci and underlying molecular mechanisms are poorly understood.Here,we utilized a Bayesian approach,integrative risk gene selector(iRIGS),to prioritize risk genes at CRC GWAS loci by integrating multi-omics data.As a result,a total of 105 high-confidence risk genes(HRGs)were identified,which exhibited strong gene dependencies for CRC and enrichment in the biological processes implicated in CRC.Among the 105 HRGs,CEBPB,located at the 20q13.13 locus,acted as a transcription factor playing critical roles in cancer.Our subsequent assays indicated the tumor promoter function of CEBPB that facilitated CRC cell proliferation by regulating multiple oncogenic pathways such as MAPK,PI3K-Akt,and Ras signaling.Next,by integrating a fine-mapping analysis and three independent case-control studies in Chinese populations consisting of 8,039 cases and 12,775 controls,we elucidated that rs1810503,a putative functional variant regulating CEBPB,was associated with CRC risk(OR=0.90,95%CI=0.86–0.93,P=1.07×10^(−7)).The association between rs1810503 and CRC risk was further validated in three additional multi-ancestry populations consisting of 24,254 cases and 58,741 controls.Mechanistically,the rs1810503 A to T allele change weakened the enhancer activity in an allele-specific manner to decrease CEBPB expression via longrange promoter-enhancer interactions,mediated by the transcription factor,REST,and thus decreased CRC risk.In summary,our study provides a genetic resource and a generalizable strategy for CRC etiology investigation,and highlights the biological implications of CEBPB in CRC tumorigenesis,shedding new light on the etiology of CRC.
基金supported by the National Key R&D Program of China (2022YFF1000100 to Long Jin and 2023YFD1300012 to Long Jin)the Sichuan Science and Technology Program (2022JDJQ0054 to Long Jin and 2021YFYZ0009 to Mingzhou Li)the National Natural Science Foundation of China (32225046 to Mingzhou Li)。
文摘Background Goose, descendants of migratory ancestors, have undergone extensive selective breeding, resulting in their remarkable ability to accumulate fat in the liver and exhibit a high tolerance for significant energy intake. As a result, goose offers an excellent model for studying obesity, metabolic disorders, and liver diseases in mammals. Although the impact of the three-dimensional arrangement of chromatin within the cell nucleus on gene expression and transcriptional regulation is widely acknowledged, the precise functions of chromatin architecture reorganization during fat deposition in goose liver tissues still need to be fully comprehended.Results In this study, geese exhibited more pronounced changes in the liver index and triglyceride(TG) content following the consumption of the high-fat diet(HFD) than mice without significant signs of inflammation. Additionally, we performed comprehensive analyses on 10 goose liver tissues(5 HFD, 5 normal), including generating highresolution maps of chromatin architecture, conducting whole-genome gene expression profiling, and identifying H3K27ac peaks in the livers of geese and mice subjected to the HFD. Our results unveiled a multiscale restructuring of chromatin architecture, encompassing Compartment A/B, topologically associated domains, and interactions between promoters and enhancers. The dynamism of the three-dimensional genome architecture, prompted by the HFD, assumed a pivotal role in the transcriptional regulation of crucial genes. Furthermore, we identified genes that regulate chromatin conformation changes, contributing to the metabolic adaptation process of lipid deposition and hepatic fat changes in geese in response to excessive energy intake. Moreover, we conducted a cross-species analysis comparing geese and mice exposed to the HFD, revealing unique characteristics specific to the goose liver compared to a mouse. These chromatin conformation changes help elucidate the observed characteristics of fat deposition and hepatic fat regulation in geese u
文摘目的 构建前列腺特异性膜抗原启动子增强子靶向性调控的 U PRT基因真核表达重组质粒 (p PS-MAenhancer/ promoter- U PRT)。方法 采用 PCR技术从大肠杆菌 JM10 9基因组中扩增 U PRT基因 ,通过分子克隆技术将其克隆到包括前列腺特异性膜抗原启动子增强子靶向性调控的 p EGFP- 1的质粒。利用重组质粒 p PS-MAenhancer/ promoter- U PRT)转染 L Ncap细胞 ,MTT法检测 5 -氯尿嘧啶 (5 - FU)对转染 L Ncap细胞存活率的影响。结果 质粒 p PSMAenhancer/ promoter- EGFP双酶切去除 EGFP,连接上 U PRT基因 ,成功构建 p PSMAenhancer/ promoter- UPRT,并转染 L Ncap细胞 ,使 L Ncap细胞对 5 - FU的杀伤敏感性大大提高。结论 p PSMAenhancer/ promoter- U PRT的构建和表达 ,为进一步研究 UPRT基因对 5 - FU的靶向性杀伤前列腺癌细胞增强作用和对前列腺癌自杀基因系统 (CD/ 5 -FC系统 )的放大效应奠定了基础。
