SRSF2 mutations drive oncogenesis by activating a global program of aberrant alternative splicing in hematopoietic...

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• Recurrent SRSF2 mutations are linked to poor outcomes in myelodysplastic syndromes (MDS).
• The precise molecular mechanisms driving oncogenesis by SRSF2 mutations remain unclear.
• Investigating whether SRSF2 mutations directly impact splicing or affect a broader network is crucial.

Purpose of the Study:

• To elucidate the global effects of SRSF2 mutations on RNA binding and splicing in vivo.
• To determine the downstream consequences of SRSF2 mutations on gene regulatory networks.
• To understand the role of altered splicing in MDS pathogenesis.

Main Methods:

• Utilized HITS-CLIP (High-Throughput Sequencing of RNA with Crosslinking and Immunoprecipitation) to map SRSF2 binding sites genome-wide.
• Analyzed differential binding events and their correlation with alternative splicing.
• Investigated the impact of specific splice alterations on hematopoietic differentiation.

Main Results:

• SRSF2 mutations primarily affect RNA binding, with most differential binding events not leading to direct alternative splicing of target exons.
• Alternative splicing alterations are largely driven by indirect effects.
• SRSF2 targets are enriched in RNA processing and splicing genes, indicating a 'splicing-cascade' phenotype.
• Splice alteration of HNRNPA2B1 by SRSF2 mutations impairs hematopoietic differentiation.

Conclusions:

• SRSF2 mutations initiate a cascade of gene regulatory events affecting multiple RNA processing and splicing proteins.
• This splicing cascade contributes to altered hematopoiesis and cancer development in MDS.
• The findings provide a model for how mutations in splicing factors drive oncogenesis.