Linker Histone Regulates the Myeloid Versus Lymphoid Bifurcation of Multipotent Hematopoietic Stem and Progenitors

Multipotent hematopoietic stem and progenitor cells (HSPC) give rise to both myeloid and lymphoid cells. The ratio between myeloid and lymphoid cells is controlled according to homeostatic turnover and adjusted in response to physiological signals. Functionally impaired HSPCs often skew toward the myeloid lineage, underlying disease states such as inflammation and cancer. The molecular mechanisms responsible for the myeloid versus lymphoid decision within the multipotent HSPCs remains poorly understood, and intervention strategies to mitigate this lineage skewing are limited. Here we report that linker histone regulates HSPCs at the lymphoid versus myeloid fate bifurcation. Chromatin DNA is packaged as nucleosomes by core histones (H2A, H2B, H3 and H4) and linker histones (H1), with H1 binding to or around the DNA dyad. H1s are highly conserved and their binding stabilizes nucleosomes, increases chromatin folding/compaction, and is associated with a transcriptionally repressed state. While genetic inactivation of any single linker histone genes yields little phenotype, simultaneous inactivation of three H1 genes (H1c-/-/H1dD/D/H1e-/-, TKO) in the hematopoietic lineages severely compromised the lymphoid lineages, as reported by Willcockson et al 2021. However, whether this apparent myeloid skewing originated from HSPCs remains known. We established a doxycycline inducible H1.0 transgene, tagged with GFP, to facilitate the manipulation and tracking of the H1.0 protein. Using this mouse model, we examined the myeloid versus lymphoid fate choice of HSPCs and found that H1.0 high HSPCs favor the lymphoid fate, in association with strengthened nucleosome organization and repression of key myeloid driver genes. Furthermore, H1.0 is turned over in response to interferon signaling, and protease inhibitors preserve endogenous H1.0 levels and promote the lymphoid fate of wild type HSPCs. Thus, we propose a molecular model that connects inflammatory signals to the impaired lineage potential of HSPCs resulting in myeloid skewing. Our work uncovers a point of pharmacologic intervention to mitigate myeloid skewed hematopoiesis.