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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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Chromatin state conservationa, Combinatorial patterns of seven histone modifications profiled were used to define promoter (1-3; A, active; D, downstream; U, upstream), gene body (4-6; tx, transcribed, 3P, 3 prime), enhancer (7-9; G, genic, 1 = strong, 2 = weak), bivalent (10), repressed Polycomb (11), heterochromatin (12), and low signal (13-14) chromatin states. Darker blue indicates a higher enrichment of the measured histone mark (x axis) to be found in a particular state (y-axis). b, Promoter, enhancer, and repressed chromatin states in mouse hippocampus (rows), as profiled in this study, align to matching chromatin states in human (columns), as profiled by the Roadmap Epigenomics Consortium10. Shading indicates enrichment relative to human chromatin state abundance (columns). The number of regions overlapping is shown in each cell of the heatmap.
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Figure 6: Chromatin state conservationa, Combinatorial patterns of seven histone modifications profiled were used to define promoter (1-3; A, active; D, downstream; U, upstream), gene body (4-6; tx, transcribed, 3P, 3 prime), enhancer (7-9; G, genic, 1 = strong, 2 = weak), bivalent (10), repressed Polycomb (11), heterochromatin (12), and low signal (13-14) chromatin states. Darker blue indicates a higher enrichment of the measured histone mark (x axis) to be found in a particular state (y-axis). b, Promoter, enhancer, and repressed chromatin states in mouse hippocampus (rows), as profiled in this study, align to matching chromatin states in human (columns), as profiled by the Roadmap Epigenomics Consortium10. Shading indicates enrichment relative to human chromatin state abundance (columns). The number of regions overlapping is shown in each cell of the heatmap.

Mentions: For epigenome analysis, we used chromatin immunoprecipitation sequencing (ChIP-seq) to profile seven chromatin marks9: H3K4me3 (associated primarily with active promoters); H3K4me1 (enhancers); H3K27ac (enhancer/promoter activation); H3K27me3 (Polycomb repression); H3K36me3 and H4K20me1 (transcription); and H3K9me3 (heterochromatin) (Extended Data Fig. 1a). We used ChromHMM (http://compbio.mit.edu/ChromHMM/) to learn a chromatin state model (see Methods, Extended Data Fig. 3a) defined by recurrent combinations of histone modifications, consisting of promoters, enhancers, transcribed, bivalent, repressed, heterochromatin and low-signal states (Extended Data Fig. 3a). We defined 57,840 active promoters using H3K4me3 peaks within promoter chromatin states, and 151,447 active enhancer regions using H3K27ac peaks within enhancer chromatin states (Extended Fig. 1a; Supplementary Table 3; see Methods).


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)

Chromatin state conservationa, Combinatorial patterns of seven histone modifications profiled were used to define promoter (1-3; A, active; D, downstream; U, upstream), gene body (4-6; tx, transcribed, 3P, 3 prime), enhancer (7-9; G, genic, 1 = strong, 2 = weak), bivalent (10), repressed Polycomb (11), heterochromatin (12), and low signal (13-14) chromatin states. Darker blue indicates a higher enrichment of the measured histone mark (x axis) to be found in a particular state (y-axis). b, Promoter, enhancer, and repressed chromatin states in mouse hippocampus (rows), as profiled in this study, align to matching chromatin states in human (columns), as profiled by the Roadmap Epigenomics Consortium10. Shading indicates enrichment relative to human chromatin state abundance (columns). The number of regions overlapping is shown in each cell of the heatmap.
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Related In: Results  -  Collection

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Figure 6: Chromatin state conservationa, Combinatorial patterns of seven histone modifications profiled were used to define promoter (1-3; A, active; D, downstream; U, upstream), gene body (4-6; tx, transcribed, 3P, 3 prime), enhancer (7-9; G, genic, 1 = strong, 2 = weak), bivalent (10), repressed Polycomb (11), heterochromatin (12), and low signal (13-14) chromatin states. Darker blue indicates a higher enrichment of the measured histone mark (x axis) to be found in a particular state (y-axis). b, Promoter, enhancer, and repressed chromatin states in mouse hippocampus (rows), as profiled in this study, align to matching chromatin states in human (columns), as profiled by the Roadmap Epigenomics Consortium10. Shading indicates enrichment relative to human chromatin state abundance (columns). The number of regions overlapping is shown in each cell of the heatmap.
Mentions: For epigenome analysis, we used chromatin immunoprecipitation sequencing (ChIP-seq) to profile seven chromatin marks9: H3K4me3 (associated primarily with active promoters); H3K4me1 (enhancers); H3K27ac (enhancer/promoter activation); H3K27me3 (Polycomb repression); H3K36me3 and H4K20me1 (transcription); and H3K9me3 (heterochromatin) (Extended Data Fig. 1a). We used ChromHMM (http://compbio.mit.edu/ChromHMM/) to learn a chromatin state model (see Methods, Extended Data Fig. 3a) defined by recurrent combinations of histone modifications, consisting of promoters, enhancers, transcribed, bivalent, repressed, heterochromatin and low-signal states (Extended Data Fig. 3a). We defined 57,840 active promoters using H3K4me3 peaks within promoter chromatin states, and 151,447 active enhancer regions using H3K27ac peaks within enhancer chromatin states (Extended Fig. 1a; Supplementary Table 3; see Methods).

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