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

Alzheimer’s disease (AD) is a severe1 age-related neurodegenerative disorder characterized by accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles, synaptic and neuronal loss, and cognitive decline. Several genes have been implicated in AD, but chromatin state alterations during neurod...

Full description

Bibliographic Details
Main Authors:	Gjoneska, Elizabeta, Pfenning, Andreas R., Mathys, Hansruedi, Quon, Gerald, Kundaje, Anshul, Tsai, Li-Huei, Kellis, Manolis
Format:	Online
Language:	English
Published:	2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530583/

id	pubmed-4530583
recordtype	oai_dc
spelling	pubmed-45305832015-08-19 Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease Gjoneska, Elizabeta Pfenning, Andreas R. Mathys, Hansruedi Quon, Gerald Kundaje, Anshul Tsai, Li-Huei Kellis, Manolis Article Alzheimer’s disease (AD) is a severe1 age-related neurodegenerative disorder characterized by accumulation of amyloid-β (Aβ) 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 (eQTL), while decreasing-level enhancer orthologs show fetal-brain-specific enhancer activity. Notably, AD-associated genetic variants are specifically enriched in increasing-level enhancer orthologs 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. 2015-02-19 /pmc/articles/PMC4530583/ /pubmed/25693568 http://dx.doi.org/10.1038/nature14252 Text en Reprints and permissions information is available at www.nature.com/reprints
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Gjoneska, Elizabeta Pfenning, Andreas R. Mathys, Hansruedi Quon, Gerald Kundaje, Anshul Tsai, Li-Huei Kellis, Manolis
spellingShingle	Gjoneska, Elizabeta Pfenning, Andreas R. Mathys, Hansruedi Quon, Gerald Kundaje, Anshul Tsai, Li-Huei Kellis, Manolis Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease
author_facet	Gjoneska, Elizabeta Pfenning, Andreas R. Mathys, Hansruedi Quon, Gerald Kundaje, Anshul Tsai, Li-Huei Kellis, Manolis
author_sort	Gjoneska, Elizabeta
title	Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease
title_short	Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease
title_full	Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease
title_fullStr	Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease
title_full_unstemmed	Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease
title_sort	conserved epigenomic signals in mice and humans reveal immune basis of alzheimer’s disease
description	Alzheimer’s disease (AD) is a severe1 age-related neurodegenerative disorder characterized by accumulation of amyloid-β (Aβ) 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 (eQTL), while decreasing-level enhancer orthologs show fetal-brain-specific enhancer activity. Notably, AD-associated genetic variants are specifically enriched in increasing-level enhancer orthologs 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.
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530583/
_version_	1613257516035080192

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

Similar Items