Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease
Author(s)
Gjoneska, Elizabeta; Pfenning, Andreas R.; Mathys, Hansruedi; Quon, Gerald; Kundaje, Anshul; Tsai, Li-Huei; Kellis, Manolis; ... Show more Show less
DownloadKellis_Conserved epigenomic.pdf (2.120Mb)
OPEN_ACCESS_POLICY
Open Access Policy
Creative Commons Attribution-Noncommercial-Share Alike
Terms of use
Metadata
Show full item recordAbstract
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.
Date issued
2015-02Department
Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory; Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences; Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science; Picower Institute for Learning and MemoryJournal
Nature
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Gjoneska, Elizabeta, Andreas R. Pfenning, Hansruedi Mathys, Gerald Quon, Anshul Kundaje, Li-Huei Tsai, and Manolis Kellis. “Conserved Epigenomic Signals in Mice and Humans Reveal Immune Basis of Alzheimer’s Disease.” Nature 518, no. 7539 (February 18, 2015): 365–369.
Version: Author's final manuscript
ISSN
0028-0836
1476-4687