title: Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease.
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.
authors.affiliation: 1] The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
authors.forename: Elizabeta
authors.initials: E
authors.lastname: Gjoneska
authors.affiliation: 1] Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2] Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Pfenning
authors.affiliation: The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Mathys
authors.affiliation: 1] Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2] Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Gerald
authors.initials: G
authors.lastname: Quon
authors.affiliation: 1] Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2] Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] Department of Genetics, Department of Computer Science, Stanford University, Stanford, California 94305, USA.
authors.forename: Anshul
authors.initials: A
authors.lastname: Kundaje
authors.affiliation: 1] The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
authors.affiliation: 1] Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2] Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Manolis
authors.initials: M
authors.lastname: Kellis
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000276:immunology* / Q000503:physiopathology; D000818:Animals; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D017124:Conserved Sequence; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D057890:Epigenomics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007109:Immunity / Q000235:genetics; D008568:Memory / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D009473:Neuronal Plasticity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D002843:Chromatin; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1