Limits...
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.

Show MeSH

Related in: MedlinePlus

Weak enrichment of AD GWAS SNPs at differential CK-p25 promotersEnrichment of AD-associated SNPs (y-axis, binomial P value) in human regions orthologous to different classes of mouse promoters
© Copyright Policy - permissions-link
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4530583&req=5

Figure 10: Weak enrichment of AD GWAS SNPs at differential CK-p25 promotersEnrichment of AD-associated SNPs (y-axis, binomial P value) in human regions orthologous to different classes of mouse promoters

Mentions: To test whether the implicated regulatory regions are causal, we examined their enrichment for AD-associated variants from genome-wide association studies (GWAS). Genetic variants associated with AD in a meta-analysis of ~74,000 individuals4, were enriched in increased-level enhancer orthologs (Fig. 2c), (4.4-fold enrichment, binomial P = 1.2 × 10−10 at GWAS cutoff P < 0.001; 9.7-fold enrichment, binomial P < 3.7 × 10−6 at GWAS cutoff P < 10−5). By contrast, decreased-level enhancer orthologs were surprisingly not enriched (0.61-fold), suggesting a causal role specifically for immune-related processes. Promoter regions were only weakly enriched, strongly implicating distal enhancers in mediating AD predisposition (Extended Data Fig. 7).


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)

Weak enrichment of AD GWAS SNPs at differential CK-p25 promotersEnrichment of AD-associated SNPs (y-axis, binomial P value) in human regions orthologous to different classes of mouse promoters
© Copyright Policy - permissions-link
Related In: Results  -  Collection

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

Figure 10: Weak enrichment of AD GWAS SNPs at differential CK-p25 promotersEnrichment of AD-associated SNPs (y-axis, binomial P value) in human regions orthologous to different classes of mouse promoters
Mentions: To test whether the implicated regulatory regions are causal, we examined their enrichment for AD-associated variants from genome-wide association studies (GWAS). Genetic variants associated with AD in a meta-analysis of ~74,000 individuals4, were enriched in increased-level enhancer orthologs (Fig. 2c), (4.4-fold enrichment, binomial P = 1.2 × 10−10 at GWAS cutoff P < 0.001; 9.7-fold enrichment, binomial P < 3.7 × 10−6 at GWAS cutoff P < 10−5). By contrast, decreased-level enhancer orthologs were surprisingly not enriched (0.61-fold), suggesting a causal role specifically for immune-related processes. Promoter regions were only weakly enriched, strongly implicating distal enhancers in mediating AD predisposition (Extended Data Fig. 7).

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