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CTCF mutation at R567 causes developmental disorders via 3D genome rearrangement and abnormal neurodevelopment
Jie Zhang1,2, Gongcheng Hu3, Yuli Lu1,4
1State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
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 11th zinc finger of CTCF, by introducing this mutation into both murine models and human embryonic stem cell-derived cortical organoid models. Mice with homozygous CTCFR567W 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 CTCFR567W mutation on human neurodevelopmental disorders, paving the way for potential therapeutic interventions.
Insights
A CTCF mutation (R567W) impairs development, causing mortality and neurodevelopmental issues in mice and human organoids. This research reveals mechanisms behind CTCF-related developmental disorders.
Area of Science:
- Genomics
- Developmental Biology
- Molecular Biology
Background:
- The three-dimensional genome organization by CTCF is crucial for development.
- Clinical mutations in CTCF are associated with adverse developmental outcomes, but mechanisms are unclear.
Purpose of the Study:
- To investigate the regulatory roles of a specific CTCF R567W mutation.
- To elucidate the impact of this mutation on murine and human embryonic stem cell-derived cortical organoid models.
Main Methods:
- Introduction of the CTCF R567W mutation into murine models and human cortical organoids.
- Pathological and single-cell transcriptome analysis.
- Assessment of CTCF binding, chromatin structure, and gene expression.
Main Results:
- Homozygous CTCF R567W mice showed growth impediments, postnatal mortality, and developmental deviations in brain, heart, and lungs.
- The mutation led to premature stem cell exhaustion, accelerated GABAergic neuron maturation, and disrupted neurodevelopmental and synaptic pathways.
- CTCF R567W hindered CTCF binding to peripheral motifs, altering chromatin and gene expression, notably at the protocadherin locus. Human organoid models mirrored these effects.
Conclusions:
- The CTCF R567W mutation significantly impacts neurodevelopment, offering insights into human neurodevelopmental disorders.
- This study provides a foundation for developing potential therapeutic interventions for CTCF-related developmental conditions.
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