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Abstract:
Hematopoietic stem cells (HSCs) rely on complex regulatory networks to preserve stemness. Due to the scarcity
of HSCs, technical challenges have limited our insights into the interplay between metabolites, transcription,
and the epigenome. In this study, we generated low-input metabolomics, transcriptomics, chromatin accessibility, and chromatin immunoprecipitation data, revealing distinctmetabolic hubs that are enriched in HSCs and
their downstream multipotent progenitors. Mechanistically, we uncover a non-classical retinoic acid (RA)
signaling axis that regulates HSC function. We show that HSCs rely on Cyp26b1, an enzyme conventionally
considered to limit RA effects in the cell. In contrast to the traditional view, we demonstrate that Cyp26b1 is
indispensable for production of the active metabolite 4-oxo-RA. Further, RA receptor beta (Rarb) is required
for complete transmission of 4-oxo-RA-mediated signaling to maintain stem cells. Our findings emphasize
that a single metabolite controls stem cell fate by instructing epigenetic and transcriptional attributes.
