Comparison with Ezh2 reveals the PRC2-dependent functions of Jarid2 in hematopoietic stem Cell lineage commitment

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-independent) functions in hematopoiesis. We sought to delineate these potential PRC2-independent functions by comparing stem and progenitor cells genetically deficient for either Jarid2 or Ezh2 (enzymatic component of PRC2). Loss of Ezh2 increased myeloid differentiation but with a defect in lymphopoiesis. In contrast, loss of Jarid2 enhanced multi-lineage differentiation proportionally. Single-cell transcriptomics showed loss of Jarid2 had minimal impact across progenitor populations, but 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. These data suggest the major PRC2-dependent function of Jarid2 in hematopoietic progenitors is restriction of myeloid differentiation potential.