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Rbfox2 selectively governs hematopoietic stem cell self-renewal by regulating proteostasis

GSE210650 Mus musculus Expression profiling by high throughput sequencing 6 samples Submitted 2025/11/01 Platform GPL19057
Summary
Self-renewing hematopoietic stem cells (HSCs) generate all blood cells and give rise to long-term reconstitution of the hematopoietic system after transplantation, but the molecular mechanisms that specifically regulate HSCs remain poorly defined. Here we found that HSCs displayed a distinct mRNA alternative splicing pattern and preferentially expressed Rbfox2, an alternative splicing regulator, compared with multipotent progenitors (MPPs). Deletion of Rbfox2 from the hematopoietic compartment specifically depleted HSCs, but not progenitors in the adult bone marrow. Rbfox1 did not function redundantly with Rbfox2 in HSCs. Mechanistically, Rbfox2 loss led to proteostasis stress, including increased protein synthesis rate and accumulated misfolded/unfolded protein contents, in HSCs, but not in progenitors. Small molecules that restore proteostasis rescued HSC defects in Rbfox2-deficient mice. Our work thus reveals that HSCs, but not progenitors, selectively rely on Rbfox2 for their self-renewal and maintenance.
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Also filed as BioProject PRJNA866551 and SRA study SRP390180. Searching any of these in the dataset finder brings you back here.

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