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
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.
