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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

Relationship between changes of gene expression and regulatory regions in CK-p25 miceFor each class of gene expression change in the CK-p25 model (x axis), overlap with different histone modifications is shown (y axis) for a, H3K4me3 at promoters; b, H3K27ac at enhancers; c, H3K27me3 at Polycomb repressed regions. Histone modifications were mapped to the nearest transcription start site (Supplementary Table 3) to show the enrichment of the changing regulatory regions relative to those that are stable in CK-p25. The significance is calculated based on the hypergeometric P value of the overlap.
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Figure 8: Relationship between changes of gene expression and regulatory regions in CK-p25 miceFor each class of gene expression change in the CK-p25 model (x axis), overlap with different histone modifications is shown (y axis) for a, H3K4me3 at promoters; b, H3K27ac at enhancers; c, H3K27me3 at Polycomb repressed regions. Histone modifications were mapped to the nearest transcription start site (Supplementary Table 3) to show the enrichment of the changing regulatory regions relative to those that are stable in CK-p25. The significance is calculated based on the hypergeometric P value of the overlap.

Mentions: Genes flanking increased- and decreased-level regulatory regions (see Methods) showed consistent gene expression changes for both promoter and enhancers regions (Extended Data Fig. 5), and were consistently enriched in immune and stimulus-response functions for increased-level enhancers and promoters, and in synapse and learning-associated functions for deceased-level enhancers and promoters (Fig. 1d, e), consistent with our Gene Ontology results of changing gene expression levels.


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)

Relationship between changes of gene expression and regulatory regions in CK-p25 miceFor each class of gene expression change in the CK-p25 model (x axis), overlap with different histone modifications is shown (y axis) for a, H3K4me3 at promoters; b, H3K27ac at enhancers; c, H3K27me3 at Polycomb repressed regions. Histone modifications were mapped to the nearest transcription start site (Supplementary Table 3) to show the enrichment of the changing regulatory regions relative to those that are stable in CK-p25. The significance is calculated based on the hypergeometric P value of the overlap.
© Copyright Policy - permissions-link
Related In: Results  -  Collection

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

Figure 8: Relationship between changes of gene expression and regulatory regions in CK-p25 miceFor each class of gene expression change in the CK-p25 model (x axis), overlap with different histone modifications is shown (y axis) for a, H3K4me3 at promoters; b, H3K27ac at enhancers; c, H3K27me3 at Polycomb repressed regions. Histone modifications were mapped to the nearest transcription start site (Supplementary Table 3) to show the enrichment of the changing regulatory regions relative to those that are stable in CK-p25. The significance is calculated based on the hypergeometric P value of the overlap.
Mentions: Genes flanking increased- and decreased-level regulatory regions (see Methods) showed consistent gene expression changes for both promoter and enhancers regions (Extended Data Fig. 5), and were consistently enriched in immune and stimulus-response functions for increased-level enhancers and promoters, and in synapse and learning-associated functions for deceased-level enhancers and promoters (Fig. 1d, e), consistent with our Gene Ontology results of changing gene expression levels.

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