{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE324nnn/GSE324227/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Methylation profiling"],"species":["Mus musculus"],"gds_type":["Methylation profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE324227"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"A progeria syndrome links DNA hypermethylation to age-related pathology [EM-Seq]","description":"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.","dates":{"publication":"2026/04/27"},"accession":"GSE324227","cross_references":{"GSM":["GSM9571578","GSM9571577","GSM9571576","GSM9571575","GSM9571579","GSM9571580"],"GPL":["30172"],"GSE":["324227"],"taxon":["Mus musculus"]}}