Human AUTS2 regulates neurodevelopmental pathways via dual DNA/RNA binding.

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• The AUTS2 gene is linked to neurodevelopmental disorders like intellectual disability and autism.
• AUTS2's roles in chromatin and RNA regulation are known, but direct RNA binding in human neural progenitors was unproven.

Purpose of the Study:

• To investigate the direct RNA interactome of AUTS2 in human neural progenitor cells (NPCs).
• To elucidate the functional consequences of AUTS2 disruption on neurodevelopmental processes.
• To identify specific molecular pathways regulated by AUTS2.

Main Methods:

• Chromatin immunoprecipitation sequencing (ChIP-seq) to identify AUTS2's chromatin targets.
• Enhanced crosslinking immunoprecipitation sequencing (eCLIP-seq) to map direct RNA interactions.
• AUTS2 knockdown in NPCs to assess functional impacts and gene expression changes.

Main Results:

• AUTS2 directly binds RNA in human NPCs, establishing its RNA interactome.
• AUTS2 knockdown caused significant gene expression alterations and impaired NPC proliferation, migration, and neurite outgrowth.
• Downregulation of Wnt pathway genes, including WNT7A, was observed in AUTS2-deficient NPCs.

Conclusions:

• AUTS2 is crucial for human neurodevelopment, directly regulating RNA targets.
• The Wnt signaling pathway, particularly WNT7A, is a key mediator of AUTS2's function.
• Restoring WNT7A levels rescued cellular defects, highlighting its therapeutic potential for AUTS2-related disorders.