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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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Increasing enhancer orthologs help interpret AD-associated noncoding lociOverlap of disease-associated SNPs (top) with increasing enhancers (2nd row, red) and immune enhancers in human (CD14+ primary cells) is shown for genome-wide significant (INPP5D and CELF1 (containing the SPI1 gene); a and b) and below-significance (ABCA1; c) AD GWAS loci. Roadmap chromatin state annotations for immune cells (CD14+ primary; E029), hippocampus (E071), and fetal brain (E81), with colors as shown in the key. Light red highlight denotes increasing enhancer regions tested in luciferase assay. kb, kilobases; Mb, megabases. d, AD associated SNP rs1377416 amplifies in vitro luciferase activity of putative enhancer region 38,313–37,359 base pairs (bp) upstream of SPI1 (PU.1) gene in BV-2 cells. n=3, P < 0.0001, one-way analysis of variance (ANOVA); **P < 0.01, Tukey’s multiple comparison post-hoc test. NS, nonsignificant.
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Figure 3: Increasing enhancer orthologs help interpret AD-associated noncoding lociOverlap of disease-associated SNPs (top) with increasing enhancers (2nd row, red) and immune enhancers in human (CD14+ primary cells) is shown for genome-wide significant (INPP5D and CELF1 (containing the SPI1 gene); a and b) and below-significance (ABCA1; c) AD GWAS loci. Roadmap chromatin state annotations for immune cells (CD14+ primary; E029), hippocampus (E071), and fetal brain (E81), with colors as shown in the key. Light red highlight denotes increasing enhancer regions tested in luciferase assay. kb, kilobases; Mb, megabases. d, AD associated SNP rs1377416 amplifies in vitro luciferase activity of putative enhancer region 38,313–37,359 base pairs (bp) upstream of SPI1 (PU.1) gene in BV-2 cells. n=3, P < 0.0001, one-way analysis of variance (ANOVA); **P < 0.01, Tukey’s multiple comparison post-hoc test. NS, nonsignificant.

Mentions: On the basis of chromatin state annotations in 127 human cell types and tissues10 (Fig. 3a and Supplementary Table 4) regions orthologous to increased-level enhancers in mouse showed immune cell enhancer activity in human (P < 10−100), while orthologs of decreased-level enhancers in mouse showed fetal brain tissue enhancer activity in human (P < 10−8 consistent; P < 10−17 late-stage; Fig. 2a; Supplementary Table 4). Adult brain tissues (including hippocampus) were not as strongly enriched, suggesting changes are biased towards neuronal plasticity. These results are consistent with decreased neuronal plasticity, and increased microglial activation and proliferation during AD progression24.


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)

Increasing enhancer orthologs help interpret AD-associated noncoding lociOverlap of disease-associated SNPs (top) with increasing enhancers (2nd row, red) and immune enhancers in human (CD14+ primary cells) is shown for genome-wide significant (INPP5D and CELF1 (containing the SPI1 gene); a and b) and below-significance (ABCA1; c) AD GWAS loci. Roadmap chromatin state annotations for immune cells (CD14+ primary; E029), hippocampus (E071), and fetal brain (E81), with colors as shown in the key. Light red highlight denotes increasing enhancer regions tested in luciferase assay. kb, kilobases; Mb, megabases. d, AD associated SNP rs1377416 amplifies in vitro luciferase activity of putative enhancer region 38,313–37,359 base pairs (bp) upstream of SPI1 (PU.1) gene in BV-2 cells. n=3, P < 0.0001, one-way analysis of variance (ANOVA); **P < 0.01, Tukey’s multiple comparison post-hoc test. NS, nonsignificant.
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Related In: Results  -  Collection

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Figure 3: Increasing enhancer orthologs help interpret AD-associated noncoding lociOverlap of disease-associated SNPs (top) with increasing enhancers (2nd row, red) and immune enhancers in human (CD14+ primary cells) is shown for genome-wide significant (INPP5D and CELF1 (containing the SPI1 gene); a and b) and below-significance (ABCA1; c) AD GWAS loci. Roadmap chromatin state annotations for immune cells (CD14+ primary; E029), hippocampus (E071), and fetal brain (E81), with colors as shown in the key. Light red highlight denotes increasing enhancer regions tested in luciferase assay. kb, kilobases; Mb, megabases. d, AD associated SNP rs1377416 amplifies in vitro luciferase activity of putative enhancer region 38,313–37,359 base pairs (bp) upstream of SPI1 (PU.1) gene in BV-2 cells. n=3, P < 0.0001, one-way analysis of variance (ANOVA); **P < 0.01, Tukey’s multiple comparison post-hoc test. NS, nonsignificant.
Mentions: On the basis of chromatin state annotations in 127 human cell types and tissues10 (Fig. 3a and Supplementary Table 4) regions orthologous to increased-level enhancers in mouse showed immune cell enhancer activity in human (P < 10−100), while orthologs of decreased-level enhancers in mouse showed fetal brain tissue enhancer activity in human (P < 10−8 consistent; P < 10−17 late-stage; Fig. 2a; Supplementary Table 4). Adult brain tissues (including hippocampus) were not as strongly enriched, suggesting changes are biased towards neuronal plasticity. These results are consistent with decreased neuronal plasticity, and increased microglial activation and proliferation during AD progression24.

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