USP7 maintains hematopoietic stem cell dormancy and function by stabilizing HMGA2

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.