Grant: Project Grant

Hematopoietic stem cell (HSC) differentiation involves global changes to the epigenetic landscape, driving the activation of lineage-specific transcriptional programs. As aging progresses, alterations in the HSC epigenetic landscape shift the balance toward myeloid differentiation, leading to impaired immune function. The reliance on chromatin states for determining lineage output offers significant therapeutic potential in aging, as epigenetic aberrations are reversible and regulated dynamically by enzymatic and biochemical activities, which can be targeted with drugs. Recently, our laboratory identified the chromatin remodeling factor SMARCD1 as a master regulator of lymphoid fate determination in HSCs. Our current work further identifies E2A and PU.1 as key downstream mediators of SMARCD1's essential role in lymphoid priming. In this application, we aim to decipher the molecular mechanisms through which SMARCD1 controls HSC lineage decisions to counteract immune aging. This research will advance our understanding of the epigenetic mechanisms shaping hematopoietic tissue and could ultimately lead to improved treatment strategies for diseases linked to age-related HSC dysfunction.