HMGA1-HP1β axis regulates premature aging in Hutchinson-Gilford progeria syndrome through chromatin remodeling

Hutchinson‑Gilford progeria syndrome (HGPS) is a rare premature aging disorder caused by mutations in the LMNA gene. High mobility group A1 (HMGA1) exhibits differential expression patterns across aging models. However, its roles and mechanisms in aging remain unclear. Here, we show a positive correlation between HMGA1 and the heterochromatin protein HP1β in multiple tissues of LmnaG609G/G609G, a classic genetic mouse model of HGPS to recapitulate typical premature aging features, and naturally aging mice, and HP1β was decreased in Hmga1−/− mice. We further demonstrate that HMGA1 mitigates HGPS cellular senescence in a HP1β-dependent manner. Multi-omics reveals that HP1β downregulates angiopoietin-like protein 2 (ANGPTL2) by reducing chromatin accessibility, thereby suppressing SASP factors, and thus, alleviating senescence. Furthermore, HMGA1 stabilizes HP1β by recruiting de-ubiquitinating enzyme USP7. Based on the binding region of HMGA1 with HP1β and USP7, we develop a unique HMGA1 peptide (UHP) that prevents HP1β degradation, thereby ameliorating HGPS cellular senescence and significantly extending the lifespan of LmnaG609G/G609G mice. Our findings elucidate a critical HMGA1-HP1β axis in premature aging and suggest that therapeutic strategies based on UHP may hold promise for HGPS. Premature aging disorders and normal aging involve changes in chromatin, but the key regulators are not fully understood. Here, the authors show HMGA1 stabilizes HP1β to remodel chromatin, curb cellular aging and extend lifespan in a progeria mouse model.