Graduate Student Stanford Institute for Stem Cell Biology and Regenerative Medicine, United States
Abstract: Hematopoietic stem cells (HSCs) are crucial for maintaining the blood system through their unique abilities of self-renewal and multilineage differentiation. Our lab previously identified the transcription factor Hoxb5 as a key marker defining long-term HSCs (LT-HSCs), but its precise function in regulating stem cell behavior remains elusive. Here, we investigate the molecular mechanisms by which Hoxb5 governs LT-HSC maintenance and differentiation. Using bulk and single-cell ATAC-sequencing on rare adult bone marrow Hoxb5+ LT-HSCs and Hoxb5- short-term HSCs (ST-HSCs), we reveal distinct chromatin accessibility patterns associated with stemness and lineage commitment. Our data show that Hoxb5+ LT-HSCs exhibit restrictive chromatin states, with reduced accessibility at lymphoid-related genes, while differentiation involves the opening of genomic regions enriched for Gata and Runx transcription factor motifs. Additionally, we have developed a novel V5-tagged, AID2-degradable Hoxb5 mouse model, enabling precise identification of Hoxb5 genomic targets and assessment of its necessity in LT-HSC function. Our preliminary data highlight specific loci involved in early lineage commitment that become accessible as Hoxb5+ LT-HSCs transition toward differentiation. By combining chromatin landscape analysis with functional validation of Hoxb5 targets, this study provides new insights into the regulatory networks sustaining LT-HSCs. This research has the potential to significantly advance our understanding of hematopoietic stem cell biology and may inform future therapeutic strategies for hematological disorders.
Funding Source: This research was supported by NIH grant TL1DK139565 and the Stanford Graduate Smith Fellowship.
