Aberrant splicing of MBD1 reshapes the epigenome to drive convergent myeloerythroid defects in MDS

Splicing defects are a characteristic feature of myelodysplastic syndromes (MDS) and typically associate with specific recurrent splicing factor mutations. However, a subset of transcripts exhibit abnormal splicing regardless of mutational background, occurring even in the absence of splicing-related mutations. We identified a long isoform of Methyl-CpG-Binding Domain 1 (MBD1) as the product of one such mutation-independent splicing event. To understand whether altered MBD1 splicing contributes to hematopoietic dysfunction, we overexpressed the long (MBD1-L) and short (MBD1-S) isoforms of MBD1 in cord blood CD34+ cells. We found that the MBD1-L isoform specifically impaired reconstitution capacity in vivo, particularly in the erythroid lineage, and produced a unique pattern of transcriptomic repression on RNA-seq compared to MBD1-S.

• Type: Transcriptome Analysis
• Archive: European Genome-phenome Archive (EGA)