CTCF mutation at R567 causes developmental disorders via 3D genome rearrangement and abnormal neurodevelopment

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.