東京大学医科学研究所先端医療研究センター血液・腫瘍生物学講座昆 彩奈Ayana KonDivision of Hematology and Tumor Biology, The Institute of Medical Science,The University of TokyoAbstractMyelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by bone marrow failure, dysplasia, and progression to acute myeloid leukemia. These disorders are frequently associated with somatic mutations in RNA splicing factors, including SRSF2, U2AF1 and SF3B1. While these mutations induce distinct splicing abnormalities through altered RNA-binding specificities, mouse models harboring different splicing factor mutations exhibit similar MDS-like phenotypes. This suggests that shared downstream mechanisms beyond splicing alterations may contribute to disease pathogenesis.We previously demonstrated that Srsf2 p.P95H mutant mice develop MDS under replicative stress, primarily driven by global splicing disruption. In the present study, we generated conditional knock-in mice carrying the U2af1 p.S34F mutation, which is also commonly observed in MDS patients. These mice similarly developed MDS features following bone marrow transplantation. RNA-seq analysis revealed preferential exon skipping at 3′ splice sites, indicating that mutant U2af1 alters splice site recognition. Comparative analyses identified both shared and mutation-specific mis-spliced target genes in the Srsf2 and U2af1 hematopoietic cells.To investigate transcriptional dysregulation beyond splicing defects, we optimized the CUT&Tag method for genome-wide R-loop profiling using as few as 200,000 primary murine hematopoietic progenitor cells. We successfully detected R-loop signals enriched around transcription start sites. We plan to further explore the molecular pathogenesis of MDS by investigating how splicing factor mutations give rise to aberrant R-loop formation and contribute to the dysregulation of gene expression and post-transcriptional processes in future studies.― 154 ―遺伝子の発現・転写後調節の破綻に起因する骨髄異形成症候群の分子病態の解明Investigating the molecular pathogenesis of myelodysplastic syndromes due to dysregulated gene expression and post-transcriptional mechanisms
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