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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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Related in: MedlinePlus

Differential microglia-specific gene expression changes in the CK-p25 miceRT-qPCR of selected microglia markers and immune response genes shows upregulation of gene expression in FAC-sorted CD11b+ CD45Low microglia from 2 week induced CK-p25 mice (red bars) relative to respective controls (black bars). Actb (b-actin) was used as a negative control. Values were normalized to Cd11b expression (n=3, *P < 0.05, two-tailed t-test); NS, non-significant.
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Figure 5: Differential microglia-specific gene expression changes in the CK-p25 miceRT-qPCR of selected microglia markers and immune response genes shows upregulation of gene expression in FAC-sorted CD11b+ CD45Low microglia from 2 week induced CK-p25 mice (red bars) relative to respective controls (black bars). Actb (b-actin) was used as a negative control. Values were normalized to Cd11b expression (n=3, *P < 0.05, two-tailed t-test); NS, non-significant.

Mentions: These coordinated neuronal and immune changes are consistent with the pathophysiology of AD2 and probably reflect both cell-type-specific expression changes as well as changes in cell composition. Indeed, comparison with expression in microglia8 (the resident immune cells of the brain) shows that both, cell type composition (P = 2.7 × 10−4) and microglia-specific activation (P = 2.9 × 10−6) significantly contribute to the gene expression changes (see Methods). Additionally, reverse transcription followed by quantitative PCR (RT-qPCR) of increased-level genes in purified CD11b+ CD45low microglia populations confirms cell-type-specific activation for five of the seven microglia-specific genes tested (Extended Data Fig. 2).


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)

Differential microglia-specific gene expression changes in the CK-p25 miceRT-qPCR of selected microglia markers and immune response genes shows upregulation of gene expression in FAC-sorted CD11b+ CD45Low microglia from 2 week induced CK-p25 mice (red bars) relative to respective controls (black bars). Actb (b-actin) was used as a negative control. Values were normalized to Cd11b expression (n=3, *P < 0.05, two-tailed t-test); NS, non-significant.
© Copyright Policy - permissions-link
Related In: Results  -  Collection

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

Figure 5: Differential microglia-specific gene expression changes in the CK-p25 miceRT-qPCR of selected microglia markers and immune response genes shows upregulation of gene expression in FAC-sorted CD11b+ CD45Low microglia from 2 week induced CK-p25 mice (red bars) relative to respective controls (black bars). Actb (b-actin) was used as a negative control. Values were normalized to Cd11b expression (n=3, *P < 0.05, two-tailed t-test); NS, non-significant.
Mentions: These coordinated neuronal and immune changes are consistent with the pathophysiology of AD2 and probably reflect both cell-type-specific expression changes as well as changes in cell composition. Indeed, comparison with expression in microglia8 (the resident immune cells of the brain) shows that both, cell type composition (P = 2.7 × 10−4) and microglia-specific activation (P = 2.9 × 10−6) significantly contribute to the gene expression changes (see Methods). Additionally, reverse transcription followed by quantitative PCR (RT-qPCR) of increased-level genes in purified CD11b+ CD45low microglia populations confirms cell-type-specific activation for five of the seven microglia-specific genes tested (Extended Data Fig. 2).

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