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

Gjoneska E, Pfenning AR, Mathys H, Quon G, Kundaje A, Tsai LH, Kellis M - Nature (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

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Enrichment of tissue-specific enhancer annotations from the Roadmap Epigenomics Consortium for AD-associated SNPs and mouse enhancersEnrichment of AD-associated SNPs (y-axis, permutation P value) in tissue-specific enhancer annotations from the Roadmap Epigenomics Consortium (points), relative to their enrichment for a, increased-level and b, decreased-level (colors of different classes along y-axis) of orthologous enhancer regions in the mouse AD model (x-axis, hypergeometric P value). Linear regression trend line and R2, based on Pearson correlation is shown.
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Figure 11: Enrichment of tissue-specific enhancer annotations from the Roadmap Epigenomics Consortium for AD-associated SNPs and mouse enhancersEnrichment of AD-associated SNPs (y-axis, permutation P value) in tissue-specific enhancer annotations from the Roadmap Epigenomics Consortium (points), relative to their enrichment for a, increased-level and b, decreased-level (colors of different classes along y-axis) of orthologous enhancer regions in the mouse AD model (x-axis, hypergeometric P value). Linear regression trend line and R2, based on Pearson correlation is shown.

Mentions: Across diverse cell types and tissues, we found concordance between the enrichment for AD GWAS single nucleotide polymorphisms (SNPs) and the enrichment for increased-level enhancer orthologs (R2 = 0.49; Fig. 2d, Extended Data Fig. 8a, left and Supplementary Table 4), with CD14+ immune cells being the most enriched in both, followed by other immune cell types, and with fetal brain enhancers showing the smallest enrichment in both. By contrast, decreasing enhancers orthologs showed a very weak correlation (R2 < 0.08) (Fig. 2e, Extended Data Fig. 8b, right and Supplementary Table 4). The increased-level enhancer ortholog enrichment for AD GWAS SNPs persisted both within CD14+ enhancers (3.0-fold enrichment, binomial P = 1.3 × 10−5) and outside CD14+ enhancers (3.4-fold, P = 0.005) suggesting it is not solely a feature of CD14+ cell type enrichment (see Methods).


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

Gjoneska E, Pfenning AR, Mathys H, Quon G, Kundaje A, Tsai LH, Kellis M - Nature (2015)

Enrichment of tissue-specific enhancer annotations from the Roadmap Epigenomics Consortium for AD-associated SNPs and mouse enhancersEnrichment of AD-associated SNPs (y-axis, permutation P value) in tissue-specific enhancer annotations from the Roadmap Epigenomics Consortium (points), relative to their enrichment for a, increased-level and b, decreased-level (colors of different classes along y-axis) of orthologous enhancer regions in the mouse AD model (x-axis, hypergeometric P value). Linear regression trend line and R2, based on Pearson correlation is shown.
© Copyright Policy - permissions-link
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4530583&req=5

Figure 11: Enrichment of tissue-specific enhancer annotations from the Roadmap Epigenomics Consortium for AD-associated SNPs and mouse enhancersEnrichment of AD-associated SNPs (y-axis, permutation P value) in tissue-specific enhancer annotations from the Roadmap Epigenomics Consortium (points), relative to their enrichment for a, increased-level and b, decreased-level (colors of different classes along y-axis) of orthologous enhancer regions in the mouse AD model (x-axis, hypergeometric P value). Linear regression trend line and R2, based on Pearson correlation is shown.
Mentions: Across diverse cell types and tissues, we found concordance between the enrichment for AD GWAS single nucleotide polymorphisms (SNPs) and the enrichment for increased-level enhancer orthologs (R2 = 0.49; Fig. 2d, Extended Data Fig. 8a, left and Supplementary Table 4), with CD14+ immune cells being the most enriched in both, followed by other immune cell types, and with fetal brain enhancers showing the smallest enrichment in both. By contrast, decreasing enhancers orthologs showed a very weak correlation (R2 < 0.08) (Fig. 2e, Extended Data Fig. 8b, right and Supplementary Table 4). The increased-level enhancer ortholog enrichment for AD GWAS SNPs persisted both within CD14+ enhancers (3.0-fold enrichment, binomial P = 1.3 × 10−5) and outside CD14+ enhancers (3.4-fold, P = 0.005) suggesting it is not solely a feature of CD14+ cell type enrichment (see Methods).

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus