CTCF mutation at R567 causes developmental disorders via 3D genome rearrangement and abnormal neurodevelopment

作者：Jie Zhang, Gongcheng Hu, Yuli Lu, Huawei Ren, Yin Huang, Yulin Wen, Binrui Ji, Diyang Wang, Haidong Wang, Huisheng Liu, Ning Ma, Lingling Zhang, Guangjin Pan, Yibo Qu, Hua Wang, Wei Kevin Zhang, Zhichao Miao, Hongjie Yao · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-024-49684-1 · 被引用次数：13 · 研究领域：Genomics and Chromatin Dynamics、Epigenetics and DNA Methylation、Microtubule and mitosis dynamics

Abstract The three-dimensional genome structure organized by CTCF is required for development. Clinically identified mutations in CTCF have been linked to adverse developmental outcomes. Nevertheless, the underlying mechanism remains elusive. In this investigation, we explore the regulatory roles of a clinically relevant R567W point mutation, located within the 11 th zinc finger of CTCF, by introducing this mutation into both murine models and human embryonic stem cell-derived cortical organoid models. Mice with homozygous CTCF R567W mutation exhibit growth impediments, resulting in postnatal mortality, and deviations in brain, heart, and lung development at the pathological and single-cell transcriptome levels. This mutation induces premature stem-like cell exhaustion, accelerates the maturation of GABAergic neurons, and disrupts neurodevelopmental and synaptic pathways. Additionally, it specifically hinders CTCF binding to peripheral motifs upstream to the core consensus site, causing alterations in local chromatin structure and gene expression, particularly at the clustered protocadherin locus. Comparative analysis using human cortical organoids mirrors the consequences induced by this mutation. In summary, this study elucidates the influence of the CTCF R567W mutation on human neurodevelopmental disorders, paving the way for potential therapeutic interventions.