Early microglial priming in Alzheimer’s disease revealed by ME-seq

2026 · doi:10.64898/2026.01.30.702946
preprint OA: closed
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ME-seq, a new scalable technology, revealed that DNA methylation primes microglia for activation in Alzheimer's disease before transcriptional changes occur.

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The study developed ME-seq, a cost-reduced, scalable single-nucleus method that jointly profiles DNA methylation, gene expression, and chromatin accessibility, and applied it to build an atlas of aging and Alzheimer’s disease (AD) mouse brains with over 400,000 trimodal profiles across ages. It found that AD progression is associated with disease-specific changes in cellular composition, including accelerated epigenetic aging and expansion of disease-associated microglia (DAM), and that DNA methylation shifts occur as an early priming layer before transcriptional activation. Integrative analyses using “aging clocks” identified IRF1 as a methylation-sensitive transcription factor that gates DAM activation. The work’s limitation is that it is based on mouse data rather than direct human sampling, though it provides the first such neurodegeneration-focused trimodal atlas. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

Epigenetic modifications, particularly DNA methylation, change dynamically with aging and are implicated in Alzheimer’s Disease (AD), yet how methylation interfaces with transcriptional and chromatin regulation at single-cell resolution remains poorly understood. Progress has been limited by a lack of scalable technologies capable of jointly profiling these regulatory layers. Here, we present ME-seq, a highly scalable technologies capable of simultaneously profiling DNA methylation, gene expression, and chromatin accessibility, while achieving a 100-fold reduction in cost. We generated over 400,000 single-nucleus trimodal profiles from the aging and AD mouse brain across ages, producing the first such atlas of neurodegeneration. We found AD progression triggers pronounced, disease-specific shifts in cellular composition, characterized by accelerated epigenetic aging and the expansion of disease-associated microglia (DAM). Integrative analyses, including aging clocks, revealed that DNA methylation acts as an early priming layer preceding transcriptional activation with IRF1 identified as a methylation-sensitive transcription factor serving as a gatekeeper for DAM activation. Our results establish ME-seq as a transformative tool for large-scale epigenomic dissection, revealing DNA methylation as a primary coordinator of cell-state transitions in the aging brain. Graphic abstract
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Abstract Epigenetic modifications, particularly DNA methylation, change dynamically with aging and are implicated in Alzheimer’s Disease (AD), yet how methylation interfaces with transcriptional and chromatin regulation at single-cell resolution remains poorly understood. Progress has been limited by a lack of scalable technologies capable of jointly profiling these regulatory layers. Here, we present ME-seq, a highly scalable technologies capable of simultaneously profiling DNA methylation, gene expression, and chromatin accessibility, while achieving a 100-fold reduction in cost. We generated over 400,000 single-nucleus trimodal profiles from the aging and AD mouse brain across ages, producing the first such atlas of neurodegeneration. We found AD progression triggers pronounced, disease-specific shifts in cellular composition, characterized by accelerated epigenetic aging and the expansion of disease-associated microglia (DAM). Integrative analyses, including aging clocks, revealed that DNA methylation acts as an early priming layer preceding transcriptional activation with IRF1 identified as a methylation-sensitive transcription factor serving as a gatekeeper for DAM activation. Our results establish ME-seq as a transformative tool for large-scale epigenomic dissection, revealing DNA methylation as a primary coordinator of cell-state transitions in the aging brain. Competing Interest Statement The authors have declared no competing interest. Footnotes Lead contact: Sai Ma sai.ma2{at}mssm.edu

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