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 aging presents substantial challenges, given decades-long timescales and multifactorial origins. Epigenetic alterations have been proposed to have a key etiological 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 aging syndrome. We demonstrate that DNMT3A gain-of-function mutations in Heyn-Sproul-Jackson syndrome recapitulate age-related gains in DNA methylation (DNAme), cause multilineage stem cell dysfunction, and phenocopy aspects of aging 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 DNAme-mediated stem cell dysfunction in the etiology of medically important age-related hematological, bone and metabolic pathologies, which might be targetable by future therapies.