Journal
NATURE
Volume 518, Issue 7539, Pages 365-369Publisher
NATURE PORTFOLIO
DOI: 10.1038/nature14252
Keywords
-
Categories
Funding
- Belfer Neurodegeneration Consortium
- NIH/NINDS/NIA [RO1NS078839]
- Swiss National Science Foundation [P2BSP3_151885]
- NIH/NHGRI [R01HG004037-07, RC1HG005334]
- Swiss National Science Foundation (SNF) [P2BSP3_151885] Funding Source: Swiss National Science Foundation (SNF)
- Div Of Biological Infrastructure
- Direct For Biological Sciences [0644282] Funding Source: National Science Foundation
Ask authors/readers for more resources
Alzheimer's disease (AD) is a severe(1) age-related neurodegenerative disorder characterized by accumulation of amyloid-beta 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 down-regulation 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available