GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE324nnn/GSE324160/primaryOK200Methylation profilingMus musculusMethylation profiling by arrayhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE324160GEOGSEfalseA progeria syndrome links DNA hypermethylation to age-related pathology [mouse]Declining tissue function and regenerative capacity underlie many chronic diseases. Experimentally establishing the mechanistic basis for such tissue ageing presents substantial challenges, given decades-long timescales and multifactorial origins. Epigenetic alterations have been proposed to have a key aetiological role, but whether they are correlative or causal remains a key unanswered question, as does their contribution to specific age-related pathologies. Here, we establish a novel epigenetically-driven accelerated ageing syndrome. We demonstrate that DNMT3A gain-of-function mutations in Heyn-Sproul-Jackson syndrome recapitulate age-related gains in DNA methylation, cause multilineage stem cell dysfunction, and phenocopy aspects of ageing in humans and mice. We also show that region-specific DNA hypermethylation at lineage-specific genes can explain reduced stem cell output and lineage skewing. Hence, starting from a Mendelian disorder, we causally implicate DNA methylation-mediated stem cell exhaustion in the aetiology of medically important age-related haematological, bone and metabolic pathologies, that might be targetable by future therapies.2026/04/27GSE324160GSM9570242GSM9570243GSM9570240GSM9570241GSM9570246GSM9570247GSM9570244GSM9570245GSM9570282GSM9570283GSM9570280GSM9570281GSM9570239GSM9570237GSM9570238GSM9570253GSM9570254GSM9570251GSM9570252GSM9570213GSM9570257GSM9570214GSM9570258GSM9570255GSM9570256GSM9570212GSM9570250GSM9570248GSM9570249GSM9570220GSM9570264GSM9570265GSM9570221GSM9570262GSM9570263GSM9570224GSM9570268GSM9570225GSM9570269GSM9570222GSM9570266GSM9570267GSM9570223GSM9570260GSM9570261GSM9570217GSM9570218GSM9570259GSM9570215GSM9570216GSM9570219GSM9570231GSM9570275GSM9570276GSM9570232GSM9570273GSM9570230GSM9570274GSM9570279GSM9570235GSM9570236GSM9570233GSM9570277GSM9570234GSM9570278GSM9570271GSM9570272GSM9570270GSM9570228GSM9570229GSM9570226GSM957022732685324160Mus musculus