Nature genetics · 2026

A progeria syndrome links DNA hypermethylation to age-related pathology.

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Sarni Dan, Neary Gráinne, Carroll Paula L, Vink Chris S, Billard Caroline V, Isobe Tomoya, Weng Xiong, Portman Jordan R, McCartney Daniel L, Heyn Patricia, van 't Hof Rob J, Morrison Linda R, Martin Carol-Anne, Stok Colin, Harley Margaret E, Leitch Andrea, van den Ancker Maarten, Robertson Nic, Kitto Laura, Clark Richard, Rennie Michael, Popravko Anna, McClure Jessica J, Parry David A, Camiolo Giuseppina, Leah Tom, Jakobczyk Hélène, Megaw Roly, McKie Lisa, Marshall Grant F, Balkic Nika, Amiel Jeanne, Barragán Arévalo Tania, Bronken McCarthy Grace, Buchanan Catherine A, Buffet Alexandre, Cascón Alberto, Cogne Benjamin, Conrad Solene, Cueto-González Anna Maria, Currás-Freixes Maria, Houge Gunnar Douzgos, Fong Chin-To, George-Abraham Jaya K, Gibson Kate, Ibáñez Lourdes, Longo Nicola, Lussey-Lepoutre Charlotte, Miller Bradley S, Moles-Fernandez Alejandro, Pillai Nishitha R, Tvrdik Tatiana, Vincent Marie, Yokoyama Emiy, Abbott Catherine M, Sanchez-Luque Francisco Jose, Ottersbach Katrin, De Bari Cosimo, Roelofs Anke J, Tillotson Rebekah, Kranc Kamil R, Brown Sara J, Marioni Riccardo E, Crisan Mihaela, Göttgens Berthold, Henderson Neil C, Semple Robert K, Myant Kevin B, Dzierzak Elaine, Reijns Martin A M, Sproul Duncan, Jackson Andrew P

Аннотация

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.

Предметные рубрики MeSH

Animals Progeria DNA Methylation Humans Aging Mice DNA Methyltransferase 3A DNA (Cytosine-5-)-Methyltransferases Epigenesis, Genetic Mutation Stem Cells Female Syndrome Cell Lineage

A progeria syndrome links DNA hypermethylation to age-related pathology.

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Аннотация

Предметные рубрики MeSH