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| Status |
Public on Feb 18, 2015 |
| Title |
Conserved epigenomic signatures between mouse and human elucidate immune basis of Alzheimer's disease |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Alzheimer’s disease (AD) is a severe1 age-related neurodegenerative disorder characterized by accumulation of beta-amyloid (Aβ) 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 (eQTL), while decreasing-level enhancer orthologs show fetal brain specific enhancer activity. Surprisingly, AD-associated genetic variants are specifically enriched in increasing-level enhancer orthologs 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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| Overall design |
We profiled gene expression levels through RNA-Seq and histone mark levels through ChIP-Seq to compare control mice to the CK-p25 Alzheimer's disease model at 2 weeks and 6 weeks after induction of neurodegeneration.
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| Contributor(s) |
Gjoneska E, Pfenning AR, Kundaje A, Tsai L, Kellis M |
| Citation(s) |
25693568 |
| |
| Submission date |
Jan 21, 2015 |
| Last update date |
May 21, 2019 |
| Contact name |
Andreas R Pfenning |
| E-mail(s) |
apfenning@gmail.com
|
| Organization name |
Massachusetts Institute of Technology
|
| Department |
CSAIL
|
| Lab |
Kellis
|
| Street address |
Computer Science and Artificial Intelligence Laboratory
|
| City |
Cambridge |
| State/province |
MA |
| ZIP/Postal code |
02139 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (36)
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| Relations |
| BioProject |
PRJNA273302 |
| SRA |
SRP052717 |
| SRA |
SRP035523 |
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