KMT2D deficiency leads to cellular developmental disorders and enhancer dysregulation in neural-crest-containing brain organoids  

KMT2D缺失导致含神经嵴的类脑器官细胞发育障碍和增强子失调

作　　者：Ziyun Shan Yingying Zhao Xiuyu Chen Guodong Zhan Junju Huang Xuejie Yang Chongshen Xu Ning Guo Zhi Xiong Fang Wu Yujian Liu He Liu Biyuan Chen Bingqiu Chen Jiaoyang Sun Jiangping He Yiping Guo Shangtao Cao Kaixin Wu Rui Mao Guangming Wu Lihui Lin Xiaobing Zou Jie Wang Jiekai Chen 单紫筠;赵颖颖;陈秀玉;詹国栋;黄俊驹;杨雪洁;许崇申;郭宁;熊志;吴方;刘裕建;刘鹤;陈碧媛;陈炳秋;孙骄杨;吴凯昕;何江平;林立惠;郭宜平;曹尚涛;毛蕊;吴光明;邹小兵;汪捷;陈捷凯

机构地区：[1]Center for Cell Lineage and Development,Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine,Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine,Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences,Guangzhou 510530,China [2]Child Development and Behavior Center,The Third Affiliated Hospital,Sun Yat-sen University,Guangzhou 510630,China [3]University of Chinese Academy of Sciences,Beijing 100049,China [4]Centre for Regenerative Medicine and Health,Hong Kong Institute of Science&Innovation,Chinese Academy of Sciences,Hong Kong 999077,China [5]Center for Cell Lineage and Atlas(CCLA),Bioland Laboratory,Guangzhou 510005,China [6]Joint School of Life Sciences,Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences,Guangzhou 510530,China [7]Guangzhou Medical University,Guangzhou 511436,China [8]The Fifth Affiliated Hospital of Guangzhou Medical University,Guangzhou 510700,China [9]Guangzhou Laboratory,Guangzhou 510005,China [10]Animal Research Center,Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences,Guangzhou 510530,China

出　　处：《Science Bulletin》2024年第22期3533-3546,共14页科学通报（英文版）

基　　金：supported by National Science Foundation of China(32225012);National Key R&D Program of China(2019YFA0110200);Health@Inno HK Program launched by Innovation Technology Commission of the Hong Kong SAR,China,Youth Innovation Promotion Association,Chinese Academy of Sciences(Jie Wang),National Science Foundation of China(32000414,32000503,and 32000501);The Science and Technology Program of Guangzhou 201804020052 and 202102021039;the Pearl River Talent Recruitment Program(2021ZT09Y233);Basic Research Project of Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences,(GIBHBRP23-01,GIBHBRP23-02);Frontier Science Research Program of the CAS ZDBS-LY-SM007;Science and Technology Planning Project of Guangdong Province,China(2023B1212060050 and 2023B1212120009)。

摘　　要：KMT2D,a H3K4me1 methyltransferase primarily regulating enhancers,is a leading cause of KABUKI syndrome.This multisystem disorder leads to craniofacial and cognitive abnormalities,possibly through neural crest and neuronal lineages.However,the impacted cell-of-origin and molecular mechanism of KMT2D during the development of KABUKI disease remains unknown.Here we have optimized a brain organoid model to investigate neural crest and neuronal differentiation.To pinpoint KMT2D's enhancer target,we developed a genome-wide cis-regulatory element explorer(GREE)based on single-cell multiomic integration.Single cell RNA-seq revealed that KMT2D-knockout(KO)and patient-derived organoids exhibited neural crest deformities and GABAergic overproduction.Mechanistically,GREE identified that KMT2D targets a roof-plate-like niche cell and activates the niche cell-specific WNT3A enhancer,providing the microenvironment for neural crest and neuronal development.Interestingly,KMT2D-mutated mice displayed decreased WNT3A expression in the diencephalon roof plate,indicating impaired niche cell function.Deleting the WNT3A enhancer in the organoids presented phenotypic similarities to KMT2D-depletion,emphasizing the WNT3A enhancer as the predominant target of KMT2D.Conversely,reactivating WNT signaling in KMT2D-KO rescued the lineage defects by restoring the microenvironment.Overall,our discovery of KMT2D's primary target provides insights for reconciling complex phenotypes of KABUKI syndrome and establishes a new paradigm for dissecting the mechanisms of genetic disorders from genotype to phenotype.

关 键 词：KMT2D ENHANCER NICHE Cerebral organoids Single-cell multiome 

分 类 号：R741[医药卫生—神经病学与精神病学]