Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease

Elizabeta Gjoneska, Andreas R. Pfenning, Hansruedi Mathys, Gerald Quon, Anshul Kundaje, Li Huei Tsai, Manolis Kellis

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Abstract

Alzheimer's disease (AD) is a severe age-related neurodegenerative disorder characterized by accumulation of amyloid-β plaques and neurofibrillary tangles, synaptic and neuronal loss, and cognitive decline. Several genes have been implicated in AD, but chromatin state alterations during neurodegeneration remain uncharacterized. Here we profile transcriptional and chromatin state dynamics across early and late pathology in the hippocampus of an inducible mouse model of AD-like neurodegeneration. We find a coordinated downregulation of synaptic plasticity genes and regulatory regions, and upregulation of immune response genes and regulatory regions, which are targeted by factors that belong to the ETS family of transcriptional regulators, including PU.1. Human regions orthologous to increasing-level enhancers show immune-cell-specific enhancer signatures as well as immune cell expression quantitative trait loci, while decreasing-level enhancer orthologues show fetal-brain-specific enhancer activity. Notably, AD-associated genetic variants are specifically enriched in increasing-level enhancer orthologues, implicating immune processes in AD predisposition. Indeed, increasing enhancers overlap known AD loci lacking protein-altering variants, and implicate additional loci that do not reach genome-wide significance. Our results reveal new insights into the mechanisms of neurodegeneration and establish the mouse as a useful model for functional studies of AD regulatory regions.

Original languageEnglish (US)
Pages (from-to)365-369
Number of pages5
JournalNature
Volume518
Issue number7539
DOIs
StatePublished - Feb 19 2015
Externally publishedYes

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Cite this

Gjoneska, E., Pfenning, A. R., Mathys, H., Quon, G., Kundaje, A., Tsai, L. H., & Kellis, M. (2015). Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease. Nature, 518(7539), 365-369. https://doi.org/10.1038/nature14252