Research

Most vertebrate genes contain non-coding introns that must be removed from pre-mRNA via splicing before translation. This process is carried out by a highly conserved and intricate machinery involving over 200 proteins and five small nuclear RNAs (snRNAs). Recurrent mutations in key spliceosomal components—including SF3B1, SRSF2, U2AF1, and U1 snRNA—have been identified in clonal hematopoietic disorders such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Our lab investigates how these mutations disrupt the coordination between splicing and transcription, revealing that mutant splicing factors not only alter alternative splicing but also fundamentally impair transcriptional kinetics.

While most introns are excised during mRNA processing, some are selectively retained, giving rise to intron-retaining transcripts (IR-RNAs). Once thought to be splicing errors, these transcripts are now recognized as a regulated layer of gene expression. Intron retention is especially pronounced during erythroid maturation. We study how this process is dynamically regulated during normal erythropoiesis, how it shapes erythroid-specific gene expression programs, and how its dysregulation contributes to MDS pathogenesis.

The bone marrow microenvironment (ME) consists of diverse cell types—including stromal cells, macrophages, endothelial cells, and osteoblasts—that collectively support hematopoietic stem and progenitor cells (HSPCs). Among these, mesenchymal progenitor cells (MPCs) are major producers of critical factors such as CXCL12 and stem cell factor (SCF). Yet, little is known about how transcription of such factors is coordinated across ME cell types. We are applying functional genomic screens and hematopoietic assays to identify the transcription factors that drive niche-specific gene expression. Our long-term goal is to reprogram fibroblasts into MPC-like cells capable of supporting HSPCs and to restore niche function in diseases such as myelofibrosis.