Chromodomain helicase DNA binding protein 7(CHD7),an ATP-dependent chromatin remodeler,plays versatile roles in neurodevelopment.However,the functional significance of its ATPase/nucleosome remodeling activity remains...Chromodomain helicase DNA binding protein 7(CHD7),an ATP-dependent chromatin remodeler,plays versatile roles in neurodevelopment.However,the functional significance of its ATPase/nucleosome remodeling activity remains incompletely understood.Here,we generate genetically engineered mouse embryonic stem cell lines harboring either an inducible Chd7 knockout or an ATPase-deficient missense variant identified in individuals with CHD7-related disorders.Through in vitro neural induction and differentiation assays combined with mouse brain analyses,we demonstrate that CHD7 enzymatic activity is indispensable for gene regulation and neurite development.Mechanistic studies integrating transcriptomic and epigenomic profiling reveal that CHD7 enzymatic activity is essential for establishing a permissive chromatin landscape at target genes,marked by the open chromatin architecture and active histone modifications.Collectively,our findings underscore the pivotal role of CHD7 enzymatic activity in neurodevelopment and provide critical insights into the pathogenic mechanisms of CHD7 missense variants in human diseases.展开更多
The leaf is a major organ for photosynthesis,and its shape plays an important role in plant development and yield determination in rice(Oryza sativa L.).In this study,an adaxial curled leaf mutant,termed curly leaf 1-...The leaf is a major organ for photosynthesis,and its shape plays an important role in plant development and yield determination in rice(Oryza sativa L.).In this study,an adaxial curled leaf mutant,termed curly leaf 1-1(cul1-1),was obtained by chemical mutagenesis.The leaf rolling index of the cul1-1 mutant was higher than that of the wild-type,which was caused by the abnormal development of bulliform cells(BCs).We cloned the CUL1 gene by map-based cloning.A nonsense mutation was present in the cul1-1 mutant,converting a tryptophan codon into a stop codon.The CUL1 gene encodes a chromodomain,helicase/ATPase and DNA-binding domain containing protein.Genes related to leaf rolling and BC development,such as ADL1,REL1 and ROC5,were activated by the cul1-1 mutation.The trimethylation of lysine 27 in histone 3(H3K27me3),but not H3K4me3,at the ADL1,REL1 and ROC5 loci,was reduced in the cul1-1 mutant.High-throughput mRNA sequencing indicated that the cul1-1 mutation caused genome-wide differential gene expression.The differentially expressed genes were classified into a few gene ontology terms and Kyoto encyclopedia of genes and genomes pathways.In the natural population,22 missense genomic variations in the CUL1 locus were identified,which composed of 7 haplotypes.A haplotype network was also built with haplotype II as the ancestor.The findings revealed that CUL1 is essential for normal leaf development and regulates this process by inhibiting the expression of genes involved in leaf rolling and BC development.展开更多
Background:Given the pervasive issues of obesity and diabetes both in Puerto Rico and the broader United States,there is a compelling need to investigate the intricate interplay among body mass index(BMI),pregesta-tio...Background:Given the pervasive issues of obesity and diabetes both in Puerto Rico and the broader United States,there is a compelling need to investigate the intricate interplay among body mass index(BMI),pregesta-tional,and gestational maternal diabetes,and their potential impact on the occurrence of congenital heart defects(CHD)during neonatal development.Methods:Using the comprehensive System of Vigilance and Surveillance of Congenital Defects in Puerto Rico,we conducted a focused analysis on neonates diagnosed with CHD between 2016 and 2020.Our assessment encompassed a range of variables,including maternal age,gestational age,BMI,pregestational diabetes,gestational diabetes,hypertension,history of abortion,and presence of preeclampsia.Results:A cohort of 673 patients was included in our study.The average maternal age was 26 years,within a range of 22 to 32 years.The mean gestational age measured 39 weeks,with a median span of 38 to 39 weeks.Of the 673 patients,274(41%)mothers gave birth to neonates diagnosed with CHD.Within this group,22 cases were linked to pre-gestational diabetes,while 202 were not;20 instances were associated with gestational diabetes,compared to 200 without;and 148 cases exhibited an overweight or obese BMI,whereas 126 displayed a normal BMI.Conclusion:We identified a statistically significant correlation between pre-gestational diabetes mellitus and the occurrence of CHD.However,our analysis did not show a statistically significant association between maternal BMI and the likelihood of CHD.These results may aid in developing effective strategies to prevent and manage CHD in neonates.展开更多
基金supported by the Medical Science Data Center at Shanghai Medical College of Fudan Universitysupported by grants from National Natural Science Foundation of China (81974229and 82171167 to W.F.,82330049 to W.Z.)+2 种基金Xiamen Municipal Major Project of High-Quality Development of Health and Wellness Technology Program (2024-GZL-GD06 to W.F.)National Key R&D Program of China (2022YFA0806603 to W.F.)Science and Technology Program of Guangzhou,China (2024A04J4924 to C.H.)
文摘Chromodomain helicase DNA binding protein 7(CHD7),an ATP-dependent chromatin remodeler,plays versatile roles in neurodevelopment.However,the functional significance of its ATPase/nucleosome remodeling activity remains incompletely understood.Here,we generate genetically engineered mouse embryonic stem cell lines harboring either an inducible Chd7 knockout or an ATPase-deficient missense variant identified in individuals with CHD7-related disorders.Through in vitro neural induction and differentiation assays combined with mouse brain analyses,we demonstrate that CHD7 enzymatic activity is indispensable for gene regulation and neurite development.Mechanistic studies integrating transcriptomic and epigenomic profiling reveal that CHD7 enzymatic activity is essential for establishing a permissive chromatin landscape at target genes,marked by the open chromatin architecture and active histone modifications.Collectively,our findings underscore the pivotal role of CHD7 enzymatic activity in neurodevelopment and provide critical insights into the pathogenic mechanisms of CHD7 missense variants in human diseases.
基金supported by the National Natural Science Foundation of China(32070642 and 31371222 to Dr.Xiaoxue Wang)the National Key Research and Development Program from the Ministry of Science and Technology of China(2016YFD0100406 and 2017YFD0300107 to Dr.Xiaoxue Wang)the Science and Technology Department of Liaoning province(2022JH6/100100039 to Dr.Xiaoxue Wang)。
文摘The leaf is a major organ for photosynthesis,and its shape plays an important role in plant development and yield determination in rice(Oryza sativa L.).In this study,an adaxial curled leaf mutant,termed curly leaf 1-1(cul1-1),was obtained by chemical mutagenesis.The leaf rolling index of the cul1-1 mutant was higher than that of the wild-type,which was caused by the abnormal development of bulliform cells(BCs).We cloned the CUL1 gene by map-based cloning.A nonsense mutation was present in the cul1-1 mutant,converting a tryptophan codon into a stop codon.The CUL1 gene encodes a chromodomain,helicase/ATPase and DNA-binding domain containing protein.Genes related to leaf rolling and BC development,such as ADL1,REL1 and ROC5,were activated by the cul1-1 mutation.The trimethylation of lysine 27 in histone 3(H3K27me3),but not H3K4me3,at the ADL1,REL1 and ROC5 loci,was reduced in the cul1-1 mutant.High-throughput mRNA sequencing indicated that the cul1-1 mutation caused genome-wide differential gene expression.The differentially expressed genes were classified into a few gene ontology terms and Kyoto encyclopedia of genes and genomes pathways.In the natural population,22 missense genomic variations in the CUL1 locus were identified,which composed of 7 haplotypes.A haplotype network was also built with haplotype II as the ancestor.The findings revealed that CUL1 is essential for normal leaf development and regulates this process by inhibiting the expression of genes involved in leaf rolling and BC development.
基金The San Juan Bautista School of Medicine’s Institutional Review Board approved the study(EMSJBIRB-7-2021).
文摘Background:Given the pervasive issues of obesity and diabetes both in Puerto Rico and the broader United States,there is a compelling need to investigate the intricate interplay among body mass index(BMI),pregesta-tional,and gestational maternal diabetes,and their potential impact on the occurrence of congenital heart defects(CHD)during neonatal development.Methods:Using the comprehensive System of Vigilance and Surveillance of Congenital Defects in Puerto Rico,we conducted a focused analysis on neonates diagnosed with CHD between 2016 and 2020.Our assessment encompassed a range of variables,including maternal age,gestational age,BMI,pregestational diabetes,gestational diabetes,hypertension,history of abortion,and presence of preeclampsia.Results:A cohort of 673 patients was included in our study.The average maternal age was 26 years,within a range of 22 to 32 years.The mean gestational age measured 39 weeks,with a median span of 38 to 39 weeks.Of the 673 patients,274(41%)mothers gave birth to neonates diagnosed with CHD.Within this group,22 cases were linked to pre-gestational diabetes,while 202 were not;20 instances were associated with gestational diabetes,compared to 200 without;and 148 cases exhibited an overweight or obese BMI,whereas 126 displayed a normal BMI.Conclusion:We identified a statistically significant correlation between pre-gestational diabetes mellitus and the occurrence of CHD.However,our analysis did not show a statistically significant association between maternal BMI and the likelihood of CHD.These results may aid in developing effective strategies to prevent and manage CHD in neonates.
