Journal Article Ahead of print 1 citation
PubMed: 42345356 DOI: 10.1182/blood.2025032484
Translational Regulation of Sf1 Integrates Alternative Splicing and Hematopoietic Stem Cell Fate.
Blood
Authors: Vladyslava Liudkovska, Martyna Ciołek, Daniel Grygorowicz, Ankita Kumari, Sandra Irena Binias, Jan Mikołajczyk, Anna M Lenkiewicz, Anna Konturek-Ciesla, Agata Szade, Bartosz Wojtas, Remigiusz Serwa, Tomasz W Turowski, David Bryder, Krzysztof Szade, Maciej Ciesla
Affiliations
- IMol Polish Academy of Sciences, Warszawa, Poland.
- IMol PAN, Warszawa, Poland.
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warszawa, Poland.
- Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland, Warsaw, Poland.
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
- D-BSSE ETH Zurich, Basel, Switzerland.
- Jagiellonian University, Krakow, Poland.
- Lund University, LUND, Sweden.
- Jagiellonian University, Faculty of Biochemistry, Biophysics and Biotechnology, Krakow, Poland.
Abstract
The transition of hematopoietic stem cells (HSCs) from quiescence to lineage commitment requires precise post-transcriptional control, yet the contribution of mRNA isoform regulation remains poorly defined. Here, we identify a translationally controlled splicing program that contributes to HSC fate decisions. Using activity-based signatures of 305 splicing regulators, we uncover widespread post-transcriptional modulation of the spliceosome in stem and progenitor cells. The branch-point recognition factor Sf1 emerges as a key node, regulated by a conserved structured 5' UTR that cooperates with the RNA-binding protein Igf2bp2 to control its translation. Disrupting this cis-trans module reduces Sf1 protein synthesis and skews differentiation toward stem and erythroid programs. Mechanistically, Sf1-dependent alternative splicing remodels 5' UTRs of hematopoietic and DNA damage response genes, altering their translation and modulating DNA damage resolution. Together, these findings reveal an unrecognized translational layer controlling spliceosome activity and link RNA regulons, alternative splicing, and HSC fate determination.
MeSH
Cells, Hematology, Microscopy, Electron, Scanning Transmission, 5' Untranslated Regions, Stem Cells, Alternative Splicing, Spliceosomes, Hematopoietic Stem Cells, Rna