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CTCF Point Mutation at R567 Disrupts Mouse Heart Development via 3D Genome Rearrangement and Transcription
Huawei Ren1,2,3,4, Hongxin Zhong2, Jie Zhang2
1College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong, China.
Abstract:
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.
Insights
The CTCF-R567W mutation severely impacts embryonic heart development in mice, causing structural defects and gene expression changes. This CTCF mutation also impairs cardiac contractility in adult mice.
Area of Science:
- Genetics
- Developmental Biology
- Cardiology
Background:
- CCCTC-binding factor (CTCF) is crucial for chromatin organization and gene regulation.
- CTCF mutations are linked to congenital developmental disorders, including congenital cardiomyopathy.
- The specific CTCF-R567W mutation's role in heart development requires detailed investigation.
Purpose of the Study:
- To investigate the impact of the homozygous CTCF-R567W mutation on mouse embryonic heart development.
- To elucidate the molecular mechanisms underlying CTCF-R567W-associated cardiac abnormalities.
- To assess the functional consequences of heterozygous CTCF-R567W mutation on cardiac contractility.
Main Methods:
- Utilized a mouse model with homozygous (Ctcf R567W/R567W) and heterozygous (Ctcf +/R567W) CTCF-R567W mutations.
- Analyzed cardiac tissue morphology and gene expression patterns during embryonic development.
- Examined chromatin structure, including topologically associating domains (TADs) and promoter-enhancer interactions.
- Assessed cardiac contractility in adult heterozygous mice.
Main Results:
- Homozygous Ctcf R567W/R567W mutation caused significant heart development impairments, including ventricular hyperplasia and reduced cavity size.
- Downregulation of genes involved in sarcomere assembly, calcium transport, and mitochondrial function was observed in homozygous mice.
- The mutation disrupted CTCF-chromatin interactions, altered TAD structures, and diminished key promoter-enhancer interactions.
- Heterozygous Ctcf +/R567W mutation led to compromised cardiac contractility in adult mice.
Conclusions:
- The CTCF-R567W mutation significantly disrupts embryonic cardiac morphogenesis and function.
- CTCF's role in maintaining chromatin architecture is essential for normal heart development.
- CTCF-R567W serves as a critical mutation affecting both embryonic development and adult cardiac function.
