title: 5-Hydroxymethylation-associated epigenetic modifiers of Alzheimer's disease modulate Tau-induced neurotoxicity.
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.
authors.affiliation: Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322, USA.|Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
authors.forename: Alison I
authors.initials: AI
authors.lastname: Bernstein
authors.affiliation: The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China.
authors.forename: Yunting
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: R Craig
authors.initials: RC
authors.lastname: Street
authors.affiliation: Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Chemistry.|Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Dai
authors.affiliation: The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Bao
authors.affiliation: Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, GA 30322, USA.|Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA.|Department of Neurology, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Marla
authors.initials: M
authors.lastname: Gearing
authors.affiliation: Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, GA 30322, USA.|Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Lah
authors.affiliation: Department of Pathology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Nelson
authors.affiliation: Department of Chemistry.|Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL, USA.
authors.forename: Chuan
authors.initials: C
authors.lastname: He
authors.affiliation: Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, GA 30322, USA.|Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Allan I
authors.initials: AI
authors.lastname: Levey
authors.affiliation: Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Mullé
authors.affiliation: The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China duanranhui@sklmg.edu.cn peng.jin@emory.edu.
authors.forename: Ranhui
authors.initials: R
authors.lastname: Duan
authors.affiliation: Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322, USA duanranhui@sklmg.edu.cn peng.jin@emory.edu.
authors.forename: Peng
authors.initials: P
authors.lastname: Jin
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001344:Autopsy; D019175:DNA Methylation / Q000235:genetics*; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D008297:Male; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017397:Prefrontal Cortex / Q000378:metabolism / Q000473:pathology*; D025941:Protein Interaction Mapping; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016875:tau Proteins; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine