A progeria syndrome links DNA hypermethylation to age-related pathology

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 describe an 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 implicate DNA methylation-mediated stem cell dysfunction in the aetiology of medically important age-related haematological, bone and metabolic pathologies, that might be targetable by future therapies.