Translational Control of Splicing Factors Directs Hematopoietic Stem Cell Fate [scRNA-seq]

The transition of hematopoietic stem cells (HSCs) from quiescence to differentiation is essential for homeostasis. While transcriptomic control of this process has been extensively studied, the diversity of mRNA isoforms during exit from quiescence remains unexplored. Here, we identify a translationally regulated splicing program governing hematopoietic fate decisions. Splicing factors involved in branch point recognition show dynamic protein-level regulation during HSC differentiation. Among them, Sf1 is translationally controlled via a conserved, structured 5′ UTR. Disrupting translation regulation of Sf1 skews differentiation toward stem cell and erythroid programs. Sf1-dependent alternative splicing affects 5′ UTRs of hematopoietic and DNA damage response genes, altering their translation and impairing DNA damage resolution. These findings reveal an unrecognized link between translational control of spliceosome components, alternative splicing, and HSC fate decisions.