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. 2016 Jun 15;25(12):2437-2450.
doi: 10.1093/hmg/ddw109. Epub 2016 Apr 9.

5-Hydroxymethylation-associated epigenetic modifiers of Alzheimer's disease modulate Tau-induced neurotoxicity

Alison I Bernstein  1   2 , Yunting Lin  3 , R Craig Street  1 , Li Lin  1 , Qing Dai  4   5 , Li Yu  3 , Han Bao  1 , Marla Gearing  6   7   8 , James J Lah  6   7 , Peter T Nelson  9 , Chuan He  4   5 , Allan I Levey  6   7 , Jennifer G Mullé  2 , Ranhui Duan  10 , Peng Jin  11
Affiliations

5-Hydroxymethylation-associated epigenetic modifiers of Alzheimer's disease modulate Tau-induced neurotoxicity

Alison I Bernstein et al. Hum Mol Genet. .

Abstract

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive deterioration of cognitive function. Pathogenesis of AD is incompletely understood; evidence suggests a role for epigenetic regulation, in particular the cytosine modifications 5-methylcytosine and 5-hydroxymethylcytosine (5hmC). 5hmC is enriched in the nervous system and displays neurodevelopment and age-related changes. To determine the role of 5hmC in AD, we performed genome-wide analyses of 5hmC in DNA from prefrontal cortex of post-mortem AD patients, and RNA-Seq to correlate changes in 5hmC with transcriptional changes. We identified 325 genes containing differentially hydroxymethylated loci (DhMLs) in both discovery and replication datasets. These are enriched for pathways involved in neuron projection development and neurogenesis. Of these, 140 showed changes in gene expression. Proteins encoded by these genes form direct protein-protein interactions with AD-associated genes, expanding the network of genes implicated in AD. We identified AD-associated single nucleotide polymorphisms (SNPs) located within or near DhMLs, suggesting these SNPs may identify regions of epigenetic gene regulation that play a role in AD pathogenesis. Finally, using an existing AD fly model, we showed some of these genes modulate AD-associated toxicity. Our data implicate neuronal projection development and neurogenesis pathways as potential targets in AD. By incorporating epigenomic and transcriptomic data with genome-wide association studies data, with verification in the Drosophila model, we can expand the known network of genes involved in disease pathogenesis and identify epigenetic modifiers of Alzheimer's disease.

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Figures

Figure 1.
Figure 1.
Identification and characterization of DhMLs. (A) Scatterplot of normalized genome-wide 5hmC reads within each 10-kb bin. Reads were normalized to coverage. Color of each point shows the number of bins with the given number of reads. (B) Characteristics of DhMLs from each dataset identified with diffReps. (C) Annotation of DhMLs by Homer shows enrichment and depletion of DhMLs by genomic feature. (D) Genes containing DhMLs were identified by Homer annotation for each dataset, and 325 genes were identified in both datasets. (E) The number of gene ontology terms assigned to significantly enriched gene ontology term groups for DhML-containing genes identified by ClueGO. Asterisks indicate that the displayed term is the most significant gene ontology term in a related group of gene ontology terms. (F) Gene ontology network of shared genes. For simplicity, only the most significant gene ontology term for each group is shown.
Figure 2.
Figure 2.
Genomic regions containing DhMLs and AD-associated SNPs. (A) Genomic loci containing (A) BIN1; (B) MADD, MYBPC3, SPI1, CELF1, PTPMT1 and NDUFS3; (C) INPP5D and (D) FCF1. Shown in each panel are, from top to bottom: 1) ChromHMM analysis and 2) RRBS results from a Roadmap Epigenomics Project reference sample (neuronal nuclei of frontal cortex from post-mortem brain tissue of an 81-year-old male). The legend for colors of the ChromHMM track is shown at the bottom of the figure. 3) The DhMLs identified in this analysis. Blue represents loss of 5hmC in AD; red represents a gain. Shading represents the fold change (with darker colors representing larger changes). 4) AD-associated SNPs located within 50 kb of the identified DhMLs. 4) Blocks of linkage disequilibrium for the CEU population generated by the HapMap project. 5) The RefSeq gene or genes located in the visualized regions.
Figure 3.
Figure 3.
Direct PPIs between DhML-containing genes and an AD susceptibility network. Direct PPI network between genes identified as containing intragenic DhMLs in the current analysis and AD susceptibility genes generated by DAPPLE (P = 0.001). Red indicates that a gene contains a DhML. Green indicates a significant result by RNA-Seq. Blue indicates an AD susceptibility gene.
Figure 4.
Figure 4.
Enriched gene ontology terms for 140 DhML-containing genes with significant RNA-Seq results. (A) Symbols indicate terms that have been grouped. Bar length indicates the % of genes within each gene ontology term that are in the dataset. (B) Specific genes assigned to each GO term.
Figure 5.
Figure 5.
Identification of epigenetic modifiers of Tau-mediated neurotoxicity using an AD fly model. (A) Eye phenotype of 5-day-old flies expressing both Tau (wild-type or mutant) and modifiers. (B) Percentage bar chart of eye phenotypes. Data show percentage of flies divided into four grades (I, II, III and IV) on the basis of eye phenotypes. (C) Comparison of climbing ability of 5-day-old and 10-day-old Tau WT flies with the presence or absence of modifiers. Data show mean climbing time ± SEM (Student’s t-test or Mann–Whitney test (*** = P < 0.0001, ** = P < 0.01, * = P < 0.05, ns = no significant difference). Details of all the indicated genotypes in this figure are described in Supplementary Material.
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