GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE324nnn/GSE324230/primaryOK200Methylation profilingHomo sapiensMethylation profiling by genome tiling arrayhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE324230GEOGSEfalseA progeria syndrome links DNA hypermethylation to age-related pathology [human]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.2026/04/27GSE324230GSM9571596GSM9571595GSM9571594GSM9571593GSM9571600GSM9571599GSM9571598GSM9571597GSM9571604GSM9571603GSM9571602GSM9571601GSM9571608GSM9571607GSM9571606GSM957160521145324230Homo sapiens