Functional Comparison to Ezh2 Reveals PRC2-Independent Functions of Jarid2 in Hematopoietic Stem Cell Lineage Commitment
Year: 2025
Type: preprint
Abstract: SUMMARY Previous studies showed the Polycomb Repressive Complex 2 (PRC2) co-factor Jarid2 represses self-renewal transcriptional networks in mouse multipotent progenitor cells (MPPs). But only a fraction of de-repressed HSC-specific genes were associated with loss of H3K27me3, implying Jarid2 may have non-canonical (PRC2-indpendent) in hematopoiesis. Here we sought to delineate any PRC2-independnent functions by comparing stem and progenitor cells genetically deficient for either Jarid2 or Ezh2 (enzymatic component of PRC2). Loss of Ezh2 increased myeloid differentiation in transplantation assays. In contrast, loss of Jarid2 enhanced T-cell output. Single cell transcriptomics showed while loss of Jarid2 had minimal impact across progenitor populations, loss of Ezh2 led to accumulation of lymphoid-biased MPP4 cells and B-cell progenitors in the bone marrow. Functional assays confirmed a differentiation block at the pre-pro B-cell stage. The maturational arrest of Ezh2 -deficient B-cell progenitors contrasts with increased T-cell output from loss of Jarid2 , suggesting Jarid2 has non-canonical functions in hematopoiesis.
Institution: Washington University in St. Louis
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1456733111, Functions of JARID2 in Normal and Neoplastic Hematopoiesis, G7177815877, JAK/STAT signaling in the pathogenesis of DNMT3A mutant T-ALL, G8813532474, The role of Kmt2c/MLL3 in hematopoietic stem cell self-renewal, commitment and exhaustion, Inflammatory Stress Promotes Clonal Expansion of DNMT3A-mutant HSCs, Cancer Center Support Grant
OpenAlex ID: W4412501148