Dataset Information

Cross-region reduction in 5-hydroxymethylcytosine in Alzheimer's disease brain.

ABSTRACT: Epigenetic processes play a key role in the central nervous system and altered levels of 5-methylcytosine have been associated with a number of neurologic phenotypes, including Alzheimer's disease (AD). Recently, 3 additional cytosine modifications have been identified (5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine), which are thought to be intermediate steps in the demethylation of 5-methylcytosine to unmodified cytosine. Little is known about the frequency of these modifications in the human brain during health or disease. In this study, we used immunofluorescence to confirm the presence of each modification in human brain and investigate their cross-tissue abundance in AD patients and elderly control samples. We identify a significant AD-associated decrease in global 5-hydroxymethylcytosine in entorhinal cortex and cerebellum, and differences in 5-formylcytosine levels between brain regions. Our study further implicates a role for epigenetic alterations in AD.

SUBMITTER: Condliffe D

PROVIDER: S-EPMC4066184 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Cross-region reduction in 5-hydroxymethylcytosine in Alzheimer's disease brain.

Condliffe Daniel D Wong Andrew A Troakes Claire C Proitsi Petroula P Patel Yogen Y Chouliaras Leonidas L Fernandes Cathy C Cooper Jonathan J Lovestone Simon S Schalkwyk Leonard L Mill Jonathan J Lunnon Katie K

Neurobiology of aging 20140206 8

Epigenetic processes play a key role in the central nervous system and altered levels of 5-methylcytosine have been associated with a number of neurologic phenotypes, including Alzheimer's disease (AD). Recently, 3 additional cytosine modifications have been identified (5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine), which are thought to be intermediate steps in the demethylation of 5-methylcytosine to unmodified cytosine. Little is known about the frequency of these modifica ...[more]

PMID: 24679604

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Project description:ObjectiveAlzheimer's disease (AD) is a neurodegenerative disease characterized by neuropathology and cognitive decline and associated with age. The comprehensive deoxyribonucleic acid methylation (DNAm)-transcriptome profile association analysis conducted in this study aimed to establish whole-genome DNAm profiles and explore DNAm-related genes and their potential functions. More appropriate biomarkers were expected to be identified in terms of AD.Materials and methodsIllumina 450KGSE59685 dataset AD (n = 54) and HC (n = 21) and ribonucleic-acid-sequencing data GSE118553 dataset AD patients (n = 21) and HCs (n = 13) were obtained from the gene expression omnibus database before a comprehensive DNAm-transcriptome profile association analysis, and we performed functional enrichment analysis by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses (KEGG). Three transgenic mice and three wild-type mice were used to validate the hub genes.ResultsA total of 18,104 DNAm sites in healthy controls (n = 21) and AD patients (n = 54) were surveyed across three brain regions (superior temporal gyrus, entorhinal cortex, and dorsolateral prefrontal cortex). With the addition of the transcriptome analysis, eight hypomethylated-related highly expressed genes and 61 hypermethylated-related lowly expressed genes were identified. Based on 69 shared differentially methylated genes (DMGs), the function enrichment analysis indicated Guanosine triphosphate enzymes (GTPase) regulator activity, a synaptic vesicle cycle, and tight junction functioning. Following this, mice-based models of AD were constructed, and five hub DMGs were verified, which represented a powerful, disease-specific DNAm signature for AD.ConclusionThe results revealed that the cross-brain region DNAm was altered in those with AD. The alterations in DNAm affected the target gene expression and participated in the key biological processes of AD. The study provides a valuable epigenetic resource for identifying DNAm-based diagnostic biomarkers, developing effective drugs, and studying AD pathogenesis.

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Dataset Information

Cross-region reduction in 5-hydroxymethylcytosine in Alzheimer's disease brain.

Publications

Cross-region reduction in 5-hydroxymethylcytosine in Alzheimer's disease brain.

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