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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

Epigenomic and transcriptomic profiling of a mouse model of ADa, Experimental design and progression pathology in the CK-p25 mice. b, Gene expression and histone modification levels at the SPI1 locus at 6 weeks of inducible p25 overexpression. Profiled are histone marks associated with repression (blue); histone marks associated with enhancers (orange); histone marks associated with promoters (red); histone marks associated with gene bodies (green); RNA-seq (black).
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Figure 4: Epigenomic and transcriptomic profiling of a mouse model of ADa, Experimental design and progression pathology in the CK-p25 mice. b, Gene expression and histone modification levels at the SPI1 locus at 6 weeks of inducible p25 overexpression. Profiled are histone marks associated with repression (blue); histone marks associated with enhancers (orange); histone marks associated with promoters (red); histone marks associated with gene bodies (green); RNA-seq (black).

Mentions: For transcriptome analysis, we used RNA sequencing to quantify gene expression changes for 13,836 ENSEMBL genes (see Methods; Extended Data Fig. 1a; Supplementary Table 1). We found 2,815 upregulated genes and 2,310 downregulated genes in the CK-p25 AD mouse model as compared to CK littermate controls (at q < 0.01; Supplementary Table 1), which we classified into transient (2 weeks only), late-onset (6 weeks only), and consistent (both) expression classes (Fig. 1a; Extended Data Fig. 4a, Supplementary Table 1). These showed distinct functional enrichments (Fig. 1a; Supplementary Table 2), with transient-increase genes enriched in cell cycle functions (P < 10−92), consistent-increase genes enriched in immune (P < 10−10) and stimulus response functions (P < 10−4), and consistent- and late-decrease genes enriched in synaptic and learning functions (P < 10−12).


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)

Epigenomic and transcriptomic profiling of a mouse model of ADa, Experimental design and progression pathology in the CK-p25 mice. b, Gene expression and histone modification levels at the SPI1 locus at 6 weeks of inducible p25 overexpression. Profiled are histone marks associated with repression (blue); histone marks associated with enhancers (orange); histone marks associated with promoters (red); histone marks associated with gene bodies (green); RNA-seq (black).
© Copyright Policy - permissions-link
Related In: Results  -  Collection

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

Figure 4: Epigenomic and transcriptomic profiling of a mouse model of ADa, Experimental design and progression pathology in the CK-p25 mice. b, Gene expression and histone modification levels at the SPI1 locus at 6 weeks of inducible p25 overexpression. Profiled are histone marks associated with repression (blue); histone marks associated with enhancers (orange); histone marks associated with promoters (red); histone marks associated with gene bodies (green); RNA-seq (black).
Mentions: For transcriptome analysis, we used RNA sequencing to quantify gene expression changes for 13,836 ENSEMBL genes (see Methods; Extended Data Fig. 1a; Supplementary Table 1). We found 2,815 upregulated genes and 2,310 downregulated genes in the CK-p25 AD mouse model as compared to CK littermate controls (at q < 0.01; Supplementary Table 1), which we classified into transient (2 weeks only), late-onset (6 weeks only), and consistent (both) expression classes (Fig. 1a; Extended Data Fig. 4a, Supplementary Table 1). These showed distinct functional enrichments (Fig. 1a; Supplementary Table 2), with transient-increase genes enriched in cell cycle functions (P < 10−92), consistent-increase genes enriched in immune (P < 10−10) and stimulus response functions (P < 10−4), and consistent- and late-decrease genes enriched in synaptic and learning functions (P < 10−12).

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