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

Autor: Shan Z; 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; University of Chinese Academy of Sciences, Beijing 100049, China., Zhao Y; 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; University of Chinese Academy of Sciences, Beijing 100049, China; Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong 999077, China., Chen X; 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; University of Chinese Academy of Sciences, Beijing 100049, China., Zhan G; Child Development and Behavior Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China., Huang J; 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; Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou 511436, China., Yang X; 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., Xu C; 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., Guo N; 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; Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou 511436, China., Xiong Z; 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; Guangzhou Laboratory, Guangzhou 510005, China., Wu F; 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; University of Chinese Academy of Sciences, Beijing 100049, China., Liu Y; 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., Liu H; Center for Cell Lineage and Atlas (CCLA), Bioland Laboratory, Guangzhou 510005, China; The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510700, China., Chen B; Child Development and Behavior Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China., Chen B; 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; University of Chinese Academy of Sciences, Beijing 100049, China., Sun J; Guangzhou Laboratory, Guangzhou 510005, China., He J; Center for Cell Lineage and Atlas (CCLA), Bioland Laboratory, Guangzhou 510005, China; Guangzhou Laboratory, Guangzhou 510005, China., Guo Y; 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., Cao S; Guangzhou Laboratory, Guangzhou 510005, China., Wu K; Center for Cell Lineage and Atlas (CCLA), Bioland Laboratory, Guangzhou 510005, China., Mao R; Animal Research Center, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China., Wu G; Guangzhou Laboratory, Guangzhou 510005, China., Lin L; 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., Zou X; Child Development and Behavior Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China. Electronic address: zouxb@mail.sysu.edu.cn., Wang J; 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. Electronic address: wang_jie@gibh.ac.cn., Chen J; 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; University of Chinese Academy of Sciences, Beijing 100049, China; Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong 999077, China; Center for Cell Lineage and Atlas (CCLA), Bioland Laboratory, Guangzhou 510005, China; Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Medical University, Guangzhou 511436, China. Electronic address: chen_jiekai@gibh.ac.cn.
Jazyk: angličtina
Zdroj: Science bulletin [Sci Bull (Beijing)] 2024 Nov 30; Vol. 69 (22), pp. 3533-3546. Date of Electronic Publication: 2024 Sep 07.
DOI: 10.1016/j.scib.2024.09.004
Abstrakt: 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.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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