Linker histone regulates the myeloid versus lymphoid bifurcation of multipotent hematopoietic stem and progenitors

Myeloid-biased differentiation of multipotent hematopoietic stem and progenitor cells (HSPCs) occurs with aging or exhaustion. The molecular mechanism(s) responsible for this fate bias remain unclear. Here we report that linker histone regulates HSPC fate choice at the lymphoid versus myeloid bifurcation. HSPCs expressing H1.0 from a doxycycline (dox) inducible transgene favor the lymphoid fate, display strengthened nucleosome organization and reduced chromatin accessibility at genomic regions hosting key myeloid fate drivers. The transcription factor Hlf is located in one of such regions, where chromatin accessibility and gene expression is reduced in H1.0high HSPCs. Furthermore, H1.0 protein in HSPCs can decreases in an aspartyl protease dependent manner, a process enhanced in response to interferon alpha signaling. Aspartyl protease inhibitors preserve endogenous H1.0 levels and promote the lymphoid fate of wild type HSPCs. Thus, our work uncovers a point of intervention to mitigate myeloid skewed hematopoiesis.