Functional Comparison to Ezh2 Reveals PRC2-Independent Functions of Jarid2 in Hematopoietic Stem Cell Lineage Commitment

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. Competing Interest Statement The authors declare the following competing interests (unrelated to this work): G.A.C. has performed consulting and received research funding from Incyte, Ajax Therapeutics, Atavistik Bio and ReNAgade Therapeutics Management, and is a co-founder, member of the scientific advisory board and shareholder of Pairidex, Inc.