Genome-wide DNA methylation profiling in the superior temporal gyrus reveals epigenetic signatures associated with Alzheimer's disease
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE76105 | GEO | 2015/12/18
SECONDARY ACCESSION(S): PRJNA306239
REPOSITORIES: GEO
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Project description:Recent work has identified roles for environmental, genetic and epigenetic factors in AD risk. Motivated by suspected roles for epigenetic modifications in AD, we performed a genome-wide screen of DNA methylation using the Illumina Infinium HumanMethylation450 array platform on bulk tissue samples from the superior temporal gyrus (STG) of AD cases and non-demented controls. We paired a sliding window approach with linear models that account for age, gender, ethnicity, and estimated cellular proportions (neuronal vs. glial), to characterize AD-associated differentially methylated regions (DMRs). Whole DNA was extracted from STG tissue dissections collected from deceased individuals with and without Alzheimers Disease. DNA was bisulfite converted and global DNA methylation levels were assessed using Illumina Infinium HumanMethylation450 BeadChip.
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Project description:Samples from 72 AD patients and 62 age-matched cognitively normal controls were assayed using Illumina© Infinium MethylationEPIC BeadChip. We performed an epigenome-wide association study (EWAS) to evaluate the epigenetic differences using post-mortem superior temporal gyrus (STG) and inferior frontal gyrus (IFG) samples. We performed an epigenome-wide association study (EWAS) to evaluate the epigenetic differences using post-mortem superior temporal gyrus (STG) and inferior frontal gyrus (IFG) samples.
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Project description:DNA methylation (DNAm) signal from the planum temporale of superior temporal gyrus (STG) of forty-four subjects with schizophrenia (SZ) and forty-four non-psychiatric control (NPC) subjects was measured on the Illumina MethylationEPIC BeadChip Infinium (EPIC) array. Averaged, normalized beta-values at each site were correlated with dendritic spine density (DSD) previously measured per subject to identify site-specific DNAm-DSD correlations that met methylome-wide significance, or a suggestive-level of significance. We tested the hypothesis that DNAm correlates with DSD in human STG at several sites across the methylome and that this relationship is disrupted in SZ. DSD measures were available for 40 of the subjects with SZ and 40 of the NPC subjects. We found DNAm to correlate with DSD at more sites than expected by chance in NPC, but not SZ, subjects. In addition, we show that the slopes of the linear DNAm-DSD correlations differed between SZ and NPC subjects at more sites than expected by chance. Together, these data suggest that alterations in the intercation between DNAm and neurobiology in SZ may be a mechanism for SZ-related DSD reductions.
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Project description:The present study investigated the DNA methylome and hydroxymethylome, as well as unmodified cytosine in relation to Alzheimer’s disease (AD). We identified epigenetic differences between AD patients and age-matched controls in the middle temporal gyrus, in genomic regions associated with genes such as OXT, ACSL1, RHBDF2, C3, and MIR9-3HG. Interestingly, we found that OXT methylation in the blood of aged, non-demented individuals is also associated with conversion to AD dementia. The current GEO submission concerns the middle temporal gyrus Illumina HumanHT-12 V4.0 expression dataset of this study that was used to look at the correlation between the detected epigenetic changes and gene expression.
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Project description:The present study investigated the DNA methylome and hydroxymethylome, as well as unmodified cytosine in relation to Alzheimer’s disease (AD). We identified epigenetic differences between AD patients and age-matched controls in the middle temporal gyrus, in genomic regions associated with genes such as OXT, ACSL1, RHBDF2, C3, and MIR9-3HG. Interestingly, we found that OXT methylation in the blood of aged, non-demented individuals is also associated with conversion to AD dementia. The current GEO records concerns the middle temporal gyrus (ox)BS-processed Illumina 450K dataset of this study.
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Project description:We used Illumina Human HT-12 v4 arrays to compare RNA expression of middle temporal gyrus (MTG; BA21) in Alzheimer’s Disease (AD = 97) and non-demented controls (ND = 98). A total of 938 transcripts were highly differentially expressed (adj p < 0.01; log2 Fold Change (FC) ≥ |0.500|, with 411 overexpressed and 527 underexpressed in AD. Our results correlated with expression profiling in neurons from AD and ND obtained by Laser Capture Microscopy in MTG from an independent dataset (log2 FC correlation: r = 0.504; p = 2.2e-16). Additionally selected effects were validated by qPCR. ANOVA analysis yielded no difference between genders in response to AD, but some gender specific genes were detected (e.g: IL8 and AGRN in males, and HSPH1 and GRM1 in females). Several transcripts were associated with Braak Staging (e.g AEBP1 and DNALI1), ante-mortem MMSE (e.g. AEBP1 and GFAP) and Tangle density (eg. RNU1G2, and DNALI1). At the pathway level we detected enrichment of Synaptic Vesicle Processes and GABAergic transmission genes. Finally, applying the Weighted Correlation Network Analysis (WGCNA) we identified 4 expression modules enriched for neuronal and synaptic genes, mitochondria-associated membrane (MAM), chemical stimulus and olfactory receptor and non-coding RNA metabolism genes. Our results represent an extensive description of MTG mRNA profiling in a large sample of AD and ND. These data provide a list of genes associated with AD, and correlated to neurofibrillary tangles density. In addition, these data emphasize the importance of mitochondrial membranes and transcripts related to olfactory receptors in AD.
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Project description:Alternative polyadenylation (APA) contributes to post-transcriptional regulation, but its role in Alzheimer’s disease (AD) is largely unknown. Using high-resolution SQUARE multiple 3’ primer-based sequencing, we discovered massive APA differences in temporal gyrus tissues from demented AD patients compared to either healthy controls or non-demented donors with AD neuropathology (NDWP). Advanced statistics, microfluidics RT-PCR and protein measurements validated known and novel APA-modified 3’-intact transcripts. Moreover, APA modifications, more than total transcript counts, distinguished AD patients from both controls and NDWP donors and identified cell type-characteristic, cognition-associated and neuropathology-related changes. AD-enhanced APA variants included known therapeutic targets of brain, vascular and autoimmune disorders, predicting co-involvement of these target genes in AD progression; AD/NDWP increases in 3’-intact proteinopathy-related hnRNP mRNAs were inversely associated with protein decreases, whereas NDWP-potentiated cognition was accompanied by distinct ATP and mitochondrial variants. APA variations thus provide a novel resource of unique value for both basic and translational neuroscience researchers.
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Project description:Alternative polyadenylation (APA) contributes to post-transcriptional regulation, but its role in Alzheimer’s disease (AD) is largely unknown. Using high-resolution SQUARE multiple 3’ primer-based sequencing, we discovered massive APA differences in temporal gyrus tissues from demented AD patients compared to either healthy controls or non-demented donors with AD neuropathology (NDWP). Advanced statistics, microfluidics RT-PCR and protein measurements validated known and novel APA-modified 3’-intact transcripts. Moreover, APA modifications, more than total transcript counts, distinguished AD patients from both controls and NDWP donors and identified cell type-characteristic, cognition-associated and neuropathology-related changes. AD-enhanced APA variants included known therapeutic targets of brain, vascular and autoimmune disorders, predicting co-involvement of these target genes in AD progression; AD/NDWP increases in 3’-intact proteinopathy-related hnRNP mRNAs were inversely associated with protein decreases, whereas NDWP-potentiated cognition was accompanied by distinct ATP and mitochondrial variants. APA variations thus provide a novel resource of unique value for both basic and translational neuroscience researchers.
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Project description:Along with the two hallmark pathologies—intracellular neurofibrillary tangles (NFTs) and extracellular amyloid plaques—transcriptional studies suggest that Alzheimer's disease (AD) results from dysfunction of many cellular pathways including synaptic transmission, cytoskeletal dynamics, and apoptosis. While these studies consistently point to the same pathways involved in AD, there is no consensus on which genes in each pathway are disease-relevant, much less on whether these genes play causative roles or are downstream effects of disease progression. To address these issues, we have performed a large-scale transcriptional analysis in brain of individuals with advanced AD and non-demented controls, focusing specifically on CA1 and the relatively less affected CA3. For comparisons between regions and across disease status, we find consistency in both pathway enrichment as well as specific differentially expressed genes across several studies. Furthermore, genes that show decreased expression with AD progression also tend to show enrichment in CA3 (and vice versa), suggesting that transcription levels in a region may reflect that region's vulnerability to disease. In particular, we find several strong candidate vulnerability (ABCA1, MT1H, PDK4, RHOBTB3) and protection (FAM13A1, LINGO2, UNC13C) genes based on expression patterns. We have also applied weighted gene coexpression network analysis (WGCNA) to explore the pathophysiology of AD from a systems perspective, finding modules for major cell types, which each show distinct disease-relevant expression patterns. In particular, a microglial module shows increased expression in the brain of non-demented controls harboring early NFT pathology, suggesting that microglial activation is an early event in AD progression. Total RNA obtained from 60um sections of frozen human hippocampus was collected using scalpel dissection. Control and AD brains were matched for all non-disease characteristics as closely as possible. CA1 and CA3 dissections for a given individual were taken from the same section. Several region- and disease-related comparisons were performed.
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