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.

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Journal
Nature Genetics
Published
2026-06-12
DOI
https://doi.org/10.1038/s41588-026-02633-8
Primary Topic
Epigenetics and DNA Methylation
Type
article
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article

A progeria syndrome links DNA hypermethylation to age-related pathology

Nic Robertson, Martin A.M. Reijns, María Currás-Freixes, Anna Popravko et al.
Nature Genetics
Epigenetics and DNA Methylation
article

A progeria syndrome links DNA hypermethylation to age-related pathology

Nic Robertson, Martin A.M. Reijns, María Currás-Freixes, Anna Popravko, Paula L. Carroll, Bradley S. Miller, Catherine A. Buchanan, Catherine M. Abbott, Berthold Göttgens, Nishitha R. Pillai, Emiy Yokoyama, S M Brown, Lisa McKie, Katrin Ottersbach, Cosimo De Bari, David Parry, Jeanne Amiel, L. Morrison, Charlotte Lussey‐Lepoutre, Daniel L. McCartney, Anna M. Cueto‐González, Grant F. Marshall, Kevin Myant, Elaine Dzierzak, Rebekah Tillotson, Chris S. Vink, Jaya K. George‐Abraham, Andrew P. Jackson, Dan Sarni, Solène Conrad, Richard C. Clark, Kamil R. Kranc, Alejandro Moles‐Fernández, Tomoya Isobe, Riccardo E. Marioni, Anke J. Roelofs, Tatiana Tvrdik, Caroline V. Billard, Hélène Jakobczyk, Marie Vincent, Gunnar Houge, Andrea Leitch, Jessica J McClure, Mihaela Crisan, Alexandre Buffet, Francisco J. Sánchez‐Luque, Alberto Cascón, Duncan Sproul, Colin Stok, Carol-Anne Martin, Grace McCarthy, Giuseppina Camiolo, Lourdes Ibáñez, Margaret E Harley, Neil Cowan Henderson, Xiong Weng, Nicola Longo, Kate Gibson, Benjamin Cogné, Patricia Heyn, T Leah, ROBERT K. SEMPLE, Chin-To Fong, Tania Barragán Arévalo, Nika Balkic, Rob J. van ‘t Hof, Jordan R. Portman, Gráinne Neary, Michael Rennie, Laura Kitto, Maarten van den Ancker, Roly Megaw
article en

Abstract

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.

Nature Genetics
Délégation Paris 5 (FR), Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), University of Minnesota (US), Hospital Sant Joan de Déu Barcelona (ES), Fairview Health Services (US), NHS Lothian (GB), Roslin Institute (GB), Institute of Cancer Research (GB), Inserm (FR), University of California, Los Angeles (US), Queen Mary University of London (GB), Université Paris Cité (FR), Wellcome/MRC Cambridge Stem Cell Institute (GB), University of Utah (US), University of Cambridge (GB), Haukeland University Hospital (NO), Princess Alexandra Eye Pavilion (GB), Instituto de Salud Carlos III (ES), Edinburgh Cancer Research (GB), Christchurch Hospital (NZ), Sorbonne Université (FR), Spanish National Cancer Research Centre (ES), Sorbonne Paris Cité (FR), Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES), Centre de Recherche des Cordeliers (FR), La Ligue Contre le Cancer (FR), Assistance Publique – Hôpitaux de Paris (FR), Dell Children's Medical Center of Central Texas (US), Center for Human Genetics (US), MRC Centre for Regenerative Medicine (GB), Hôpital Européen (FR), National Institute of Genomic Medicine (MX), Institute of Human Genetics (PL), Zakłady Magnezytowe (Poland) (PL), Vall d'Hebron Hospital Universitari (ES), University of Minnesota Medical Center (US), Caris Life Sciences (United States) (US), Institut du Thorax (FR), Centre for Inflammation Research (GB), Instituto de Parasitología y Biomedicina "López - Neyra" (ES), Génétique Médicale & Génomique Fonctionelle (FR), Centro de Investigación Biomédica en Red de Cáncer (ES), Institute of Genetics and Cancer (GB), University of Rochester (US), ARUP Laboratories (United States) (US), Universitat de Barcelona (ES), University of Edinburgh (GB)
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