Academic Journal
Characterization of DNA methylation in PBMCs and donor-matched iPSCs shows age-related methylation is reset during stem cell reprogramming.
| Title: | Characterization of DNA methylation in PBMCs and donor-matched iPSCs shows age-related methylation is reset during stem cell reprogramming. |
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| Authors: | Reed X; Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America.; Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America., Weller CA; Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.; DataTecnica LLC, Washington, District of Columbia, United States of America., Saez-Atienzar S; Neuromuscular Disease Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America., Beilina A; Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America., Solaiman S; Neurodegenerative Diseases Research Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, United States of America., Portley M; Neurodegenerative Diseases Research Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, United States of America., Kaileh M; Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America., Roy R; Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America., Ding J; Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America., Moore AZ; Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America., Whitaker DT; Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America., Traynor BJ; Neuromuscular Disease Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America., Ferrucci L; Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America., Gibbs JR; Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America., Scholz SW; Neurodegenerative Diseases Research Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, United States of America.; Department of Neurology, Johns Hopkins University Medical Center, Baltimore, Maryland, United States of America., Cookson MR; Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America. |
| Source: | PloS one [PLoS One] 2026 Sep 08; Vol. 21 (9), pp. e0356501. Date of Electronic Publication: 2026 Sep 08 (Print Publication: 2026). |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: San Francisco, CA : Public Library of Science |
| MeSH Terms: | Induced Pluripotent Stem Cells*/metabolism , Induced Pluripotent Stem Cells*/cytology , Leukocytes, Mononuclear*/metabolism , Leukocytes, Mononuclear*/cytology , Cellular Reprogramming*/genetics , Aging*/genetics , DNA Methylation*, Humans ; Epigenesis, Genetic ; Genome-Wide Association Study ; Female |
| Abstract: | DNA methylation is an important epigenetic mechanism that helps define and maintain cellular functions. It is influenced by many factors, including environmental exposures, genotype, cell type, sex, and aging. Since age is the primary risk factor for developing neurodegenerative diseases, it is important to determine if age-related DNA methylation is retained when cells are reprogrammed to an induced Pluripotent Stem Cell (iPSC) state. Here, we selected peripheral blood mononuclear cells (PBMCs; n = 99) from a cohort of diverse and healthy individuals enrolled in the Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing (GESTALT) study to reprogram to iPSCs. After reprogramming, the resulting iPSCs were evaluated for DNA methylation signatures to determine if they reflect the confounding factors of aging and environmental effects. Data from genome-wide DNA methylation arrays in both cell types showed that age-related methylation measured by epigenetic clocks is largely reset to an early methylation age after reprogramming of PBMCs to iPSCs. We further examined the epigenetic age of each cell type using an Epigenome-wide Association Study (EWAS) and identified a set of methylation Quantitative Trait Loci in each cell type. Our results show that age-related DNA methylation is largely reset in iPSCs, and each cell type has a unique set of methylation sites that are modified by population-level genetic variation. (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.) |
| Competing Interests: | SWS receives research support from Cerevel Therapeutics. SWS is an editorial board member for JAMA Neurology and the Journal of Parkinson’s disease. SWS is a scientific advisory board member for the Lewy Body Dementia Association, the GBA1-Canada initiative, and Mission MSA. CAW is an employee of DataTecnica LLC which has received a competitive contract awarded by the National Institutes of Health to support open science research. Authors have no interests to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials. |
| Comments: | Update of: bioRxiv. 2024 Dec 13:2024.12.13.627515. doi: 10.1101/2024.12.13.627515.. (PMID: 39713361) |
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| Grant Information: | ZIA AG000931 United States ImNIH Intramural NIH HHS; ZIA NS003154 United States ImNIH Intramural NIH HHS |
| Entry Date(s): | Date Created: 20260908 Date Completed: 20260908 Latest Revision: 20260915 |
| Update Code: | 20260915 |
| PubMed Central ID: | PMC13552744 |
| DOI: | 10.1371/journal.pone.0356501 |
| PMID: | 42709743 |
| Database: | MEDLINE |
| ISSN: | 1932-6203 |
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| DOI: | 10.1371/journal.pone.0356501 |