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

By Elizabeta Gjoneska, Andreas R. Pfenning, H. Mathys, G. Quon, Anshul B Kundaje, Li-Huei Tsai, Manolis Kellis. 2015

549 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Neurology, Physiology

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Citations in the corpus

Denoising genome-wide histone ChIP-seq with convolutional neural networks (2016, methodology): “…experiments targeting these histone modiﬁcations have been used to proﬁle genome-wide chromatinstateindiversepopulationsofcelltypesandtissues(Consortium et al. , 2015), allowing us to better understand the mechanisms of development (Bernstein et al. , 2006) and disease (Gjoneska et al. , 2015).”
Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes (2015, unknown): “) based on available ChIP-seq data of chromatin marks, including H3K36me3, H4K20me1, H3K4me1, H3K27ac, H3K4me3, H3K27me3, and H3K9me3 (Figure S2A) (Ernst et al., 2011; Gjoneska et al., 2015).”
Integrative omics for health and disease (2018, methodology): “First, combining gene expression and epigenomic data, the group showed that genes that are upregulated in an Alzheimer disease mouse model show immune cell enhancer signatures 49 .”
Temporal Tracking of Microglia Activation in Neurodegeneration at Single-Cell Resolution (2017, background): “Indeed, a growing body of evidence based on genome-wide association studies, transcriptomic, and epigenomic analyses, as well as experimental evidence in mouse models, implicates immunological mechanisms and their cellular component, microglia, in the pathogenesis of Alzheimer’s disease (AD) (Gjones”
Chromatin-state discovery and genome annotation with ChromHMM (2017, unknown): “ChromHMM has had applications to studying diseases such as Alzheimer’s disease 28,29 , neurodegeneration 30 , type 2 diabetes 31 , and cancer 32–35 , among many other diseases.”
SCENIC: Single-cell regulatory network inference and clustering (2017, background): “…the predicted microglial network to previously published gene signatures of microglial “activation” in a mouse CK-p25 Alzheimer's disease (AD) model 35 , we found the microglia network to be strongly activated and the neuronal network to be down-regulated during AD progression (Figure S4),…”
Gamma frequency entrainment attenuates amyloid load and modifies microglia (2016, unknown): “This RNA-seq analysis strongly suggests that 40 Hz stimulation causes an alteration in the state of microglia, which article reSearcH is noteworthy given the accumulating evidence that microglia play a role in AD pathology 20 .”