3167 – DEVELOPMENTAL CHANGES IN THE CHROMATIN ACCESSIBILITY OF HEMATOPOIETIC STEM CELLS ARE ASSOCIATED WITH DISTINCT GENETIC PROGRAMS

Abstract

Hematopoietic stem cells (HSCs) undergo a developmental switch in neonatal mice hallmarked by a decrease in self-renewing divisions and entry into quiescence. Molecular determinants like dynamic changes in the chromatin landscape across the switch hold key insights into developmental changes in cell fate and function but remain poorly understood. Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) has emerged as a powerful tool to study chromatin accessibility in rare cells and in combination with genome-wide expression profiling has the potential to resolve cell specific transcriptional networks. To explore the regulation of the switch between fetal liver and adult bone marrow HSC states as well as during the first stages of hematopoietic differentiation, we here asses the changes in chromatin accessibility and genome-wide gene expression patterns in immunophenotypically defined HSCs and lymphoid primed multipotent progenitors (LMPPs). Chromatin accessibility unique to adult bone marrow HSCs were found to be enriched for putative binding sites of the megakaryocyte and erythroid lineage transcription factors Nuclear factor erythroid 2 (NFE2). In parallel, adult HSC gene expression and epigenetic profiles were highly enriched for the megakaryocyte gene signature which is strikingly absent in the E14.5 fetal liver. Taken together, our results identify a previously unrecognized hallmark of the developmental switch of the HSC compartment centered around acquisition of a megakaryocyte bias. These age specific features may have important implications in host response to environmental insults.