Characterization of DNA methylation in PBMCs and donor-matched iPSCs shows methylation is reset during stem cell reprogramming

Reed, X., Weller, C. A., Saez-Atienzar, S., Beilina, A., Solaiman, S., Portley, M., Kaileh, M., Roy, R., Ding, J., Moore, A. Z., Whitaker, D. T., Traynor, B. J., Gibbs, J. R., Scholz, S. W., Cookson, M. R.

National Institute on Aging · biorxiv

Paper

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 aging-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 convert to iPSCs. After reprogramming we evaluated the resulting iPSCs for DNA methylation signatures to determine if they reflect the confounding factors of age and environmental factors. We used genome-wide DNA methylation arrays in both cell types to show that the epigenetic clock is largely reset to an early methylation age after conversion of PBMCs to iPSCs. We further examined the epigenetic age of each cell type using an Epigenome-wide Association Study (EWAS). Finally, we identified a set of methylation Quantitative Trait Loci (methQTL) 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 genetically influenced.

Graphical Abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/627515v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): [email protected]@6685bdorg.highwire.dtl.DTLVardef@d6510aorg.highwire.dtl.DTLVardef@628092_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIGeneration of a population-level set of iPSC lines from healthy individuals across the lifespan C_LIO_LIAging-related features were reset based on epigenetic markers of cytosine methylation and telomere length C_LIO_LIBy comparing methQTLs in iPSC vs. their donor PBMCs, we find that detection of methQTLs reflect biological functions of different cell types C_LI

The following analysis is generated by AI and may contain errors. It is separate from the authors’ abstract and is not peer review.

Research summary

The paper is relevant to longevity research as it investigates the resetting of DNA methylation during the reprogramming of PBMCs to iPSCs, which has implications for understanding the epigenetic changes associated with aging. However, while the findings contribute to the understanding of epigenetic mechanisms in aging, they do not directly address root causes of aging or provide significant breakthroughs that could lead to lifespan extension or rejuvenation therapies. Thus, the impact is solid but limited.

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