USP7 maintains hematopoietic stem cell dormancy and function by stabilizing HMGA2

Nouhaud, A.; Diaz, A.; Bouttier, M.; Rigaud, Q.; Enfedaque, P.; Somai, H.; Hebrard, S.; Prade, N.; Dufrechou, S.; Musiani, D.; Matondo, M.; Andrieu, G.; Pasquet, M.; Largeaud, L.; Broccardo, C.; Delabesse, E.; Gerby, B.; Didier, C.

doi:10.64898/2026.07.03.731117

bioRxiv · 10.64898/2026.07.03.731117

USP7 maintains hematopoietic stem cell dormancy and function by stabilizing HMGA2

Nouhaud, A.·Diaz, A.·Bouttier, M.·Rigaud, Q.·Enfedaque, P.·Somai, H.·Hebrard, S.·Prade, N.·Dufrechou, S.·Musiani, D.·Matondo, M.·Andrieu, G.·Pasquet, M.·Largeaud, L.·Broccardo, C.·Delabesse, E.·Gerby, B.·Didier, C.

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Abstract

Hematopoietic stem cell (HSC) longevity critically depends on maintaining a deep dormant state, yet the molecular mechanisms that preserve this rare and functionally essential population remain poorly understood. Here, we identify the deubiquitinase USP7 as a key regulator of long-term HSC dormancy. Using a Usp7+/- mouse model, we uncover selective depletion of hematopoietic stem and progenitor cells (HSPCs), which is associated with impaired long-term repopulation capacity. Strikingly, H2B-GFP label-retention assays reveal a profound loss of dormant HSCs in Usp7+/- mice, demonstrating a failure to maintain the most quiescent stem cell fraction in vivo. Consistently, single-cell RNA sequencing shows erosion of the transcriptional dormancy program, linking USP7 activity to the preservation of stem cell identity at both functional and molecular levels. Mechanistically, ultra-low-input proteomic profiling and biochemical approaches identify HMGA2 as a novel USP7 substrate, suggesting that ubiquitin-dependent regulation of chromatin architecture contributes to the control of HSC dormancy. Together, our findings establish USP7 as a critical regulator of HSC dormancy, revealing a previously unrecognized post-translational mechanism controlling stem cell longevity, with implications for aging, regeneration, and hematopoietic disorders.

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Nouhaud, A., Diaz, A., Bouttier, M., Rigaud, Q., Enfedaque, P., Somai, H., Hebrard, S., Prade, N., Dufrechou, S., Musiani, D., Matondo, M., Andrieu, G., Pasquet, M., Largeaud, L., Broccardo, C., Delabesse, E., Gerby, B., Didier, C.. 2026-07-03. USP7 maintains hematopoietic stem cell dormancy and function by stabilizing HMGA2. https://doi.org/10.64898/2026.07.03.731117

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