CTCF Point Mutation at R567 Disrupts Mouse Heart Development via 3D Genome Rearrangement and Transcription Dysregulation.

Autor: Ren H; College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong, China.; State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.; State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.; School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China., Zhong H; State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China., Zhang J; State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China., Lu Y; State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China., Hu G; Department of Basic Research, Guangzhou National Laboratory, Guangzhou, China., Duan W; Department of Cardiovascular Surgery, Xijing Hospital, Xi'an, China., Ma N; School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.; Department of Basic Research, Guangzhou National Laboratory, Guangzhou, China., Yao H; State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.; Department of Basic Research, Guangzhou National Laboratory, Guangzhou, China.
Jazyk: angličtina
Zdroj: Cell proliferation [Cell Prolif] 2024 Dec 16, pp. e13783. Date of Electronic Publication: 2024 Dec 16.
DOI: 10.1111/cpr.13783
Abstrakt: CTCF plays a vital role in shaping chromatin structure and regulating gene expression. Clinical studies have associated CTCF mutations with congenital developmental abnormalities, including congenital cardiomyopathy. In this study, we investigated the impact of the homozygous CTCF-R567W (Ctcf R567W/R567W ) mutation on cardiac tissue morphogenesis during mouse embryonic development. Our results reveal significant impairments in heart development, characterised by ventricular muscle trabecular hyperplasia and reduced ventricular cavity sizes. We also observe a marked downregulation of genes involved in sarcomere assembly, calcium ion transport, and mitochondrial function in heart tissues from homozygous mice. Furthermore, the Ctcf R567W/R567W mutation disrupts CTCF's interaction with chromatin, resulting in alterations to topologically associating domain (TAD) structure within specific genomic regions and diminishing crucial promoter-enhancer interactions necessary for cardiac development. Additionally, we find that the heterozygous CTCF-R567W (Ctcf +/R567W ) mutation significantly compromises cardiac contractility in 8-week-old mice. This study elucidates the mechanism by which the CTCF-R567W mutation hampers cardiac development, underscoring the essential role of CTCF-R567 in embryonic heart development and maturation.
(© 2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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