Correcting the myeloid bias of aged HSPCs by preventing linker histone turnover

About This Grant

(PLEASE KEEP IN WORD, DO NOT PDF) Multipotent hematopoietic stem and progenitor cells (HSPCs) give rise to both myeloid and lymphoid cells. The ratio between myeloid and lymphoid cells is normally adjusted according to homeostatic tissue turnover and injury. Aged HSPCs, however, constitutively skew toward the myeloid, underlying diverse pathologic states ranging from hyperinflammation to cancer. Aged HSCs have reproducible and concerted changes in gene expression, with some of the highly expressed genes serving as markers for their identification (e.g. CD150hi marks myeloid biased HSC or my-HSC). However, due to the unclear nature why such marker genes are overly abundant in aged HSPCs, intervention approaches to target them are limited. Recently, antibody-targeted elimination based on some of these cell surface markers demonstrated rejuvenation of the hematopoietic and immune system. These proof-in-principal results highlight the untapped opportunities for leveraging the key intracellular mechanism to correct the myeloid bias of aged HSPCs. Chromatin organizes as DNA wrapping around nucleosomes, with linker histones (H1) binding to the nucleosome dyad. H1 binding stabilizes nucleosomes, compacts chromatin, reduces accessibility, and repress gene expression. We have generated a novel Dox-inducible H1.0 (iH1.0) mouse model, with which we found that H1.0-overexpressing HSPCs have reduced chromatin accessibility at many my-HSC genes, accompanied with their reduced expression. Functionally, Dox-treated (iH1.0+) HSPCs give rise to more lymphoid-fated progenitors and differentiated lymphoid cells. Importantly, we also found that H1.0 undergoes aspartyl protease mediated turnover. Therefore, we propose to test the hypothesis that the myeloid bias of aged HSCs could be corrected by preventing H1.0 turnover with protease inhibitors, including those in clinical use for decades. We propose to uncover translational opportunities to correct the myeloid bias of aged HSPCs by preserving the endogenous H1.0. We have imported the H1.0 KO mice and crossed them with the iH1.0 mice, thus establishing a spectrum of distinct H1.0 genetic dosages (null, WT, iH1.0). The effects of aspartyl protease inhibitors on HSPC lineage behavior in these mice will be tested. Successful completion of this project will reveal H1 insufficiency to be a molecular defect in aged HSCs amenable to pharmacologic intervention with clinically used protease inhibitors.