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Early microglial priming in Alzheimer's disease revealed by ME-seq
Bohan Zhu1, Anurupa Ghosh2, Zhe Wang1
1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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.
Insights
DNA methylation is a key regulator of cell changes in the aging brain and Alzheimer's Disease (AD). New ME-seq technology reveals methylation primes cells for activation, impacting neurodegeneration.
Area of Science:
- Neuroscience
- Epigenetics
- Genomics
Background:
- DNA methylation dynamics change with aging and are linked to Alzheimer's Disease (AD).
- Understanding the interplay between methylation, transcription, and chromatin at single-cell resolution is crucial but limited by current technologies.
Purpose of the Study:
- To introduce ME-seq, a scalable technology for simultaneous profiling of DNA methylation, gene expression, and chromatin accessibility.
- To create the first atlas of neurodegeneration by generating over 400,000 single-nucleus profiles from aging and AD mouse brains.
Main Methods:
- Development and application of ME-seq technology for multi-omic single-nucleus profiling.
- Generation of a large-scale dataset from aging and AD mouse brain samples.
- Integrative analysis including aging clocks and transcription factor identification.
Main Results:
- ME-seq offers a 100-fold cost reduction for simultaneous multi-omic profiling.
- Alzheimer's Disease progression induces significant, disease-specific cellular composition shifts, including accelerated epigenetic aging and expansion of disease-associated microglia (DAM).
- DNA methylation acts as an early priming signal preceding transcriptional changes, with IRF1 identified as a key regulator of DAM activation.
Conclusions:
- ME-seq is a transformative tool for large-scale epigenomic studies.
- DNA methylation plays a primary role in coordinating cell-state transitions within the aging brain and in AD.
- This study provides novel insights into the epigenetic mechanisms underlying neurodegeneration.
