The functional landscape of alternative splicing in hematopoietic lineage commitment

Area of Science:

• Molecular Biology
• Genomics
• Developmental Biology

Background:

• Alternative splicing (AS) significantly expands the proteome in vertebrates but its role in hematopoiesis is poorly understood.
• Species- and cell lineage-specific splice variants are crucial for understanding vertebrate development.

Purpose of the Study:

• To develop a computational tool for identifying functional exon skipping (ES) events in protein-coding genes during hematopoietic differentiation.
• To investigate the functional impact of AS on vertebrate hematopoiesis.

Main Methods:

• Curated transcriptomic data from six vertebrates and human/mouse hematopoietic differentiation.
• Developed a machine-learning model (FAScore) using 19 features (e.g., expression, structure, conservation) to predict functional AS.
• Investigated the functional consequences of identified AS events in erythropoiesis and myelopoiesis.

Main Results:

• Identified four novel functional AS events impacting erythropoiesis and myelopoiesis.
• Demonstrated that deletion of TBC1D23 exon 15 impairs erythropoiesis in mice and zebrafish.
• Elucidated a mechanism involving RANBP2/RANGAP1 binding and HDAC1 SUMOylation.

Conclusions:

• FAScore is a valuable tool for identifying functional ES events in hematopoietic lineage commitment.
• This study provides a framework for applying computational approaches to study AS in other biological processes.
• Discovered novel AS events with significant roles in vertebrate blood cell development.