title: Substantial DNA methylation differences between two major neuronal subtypes in human brain.
abstract: The brain is built from a large number of cell types which have been historically classified using location, morphology and molecular markers. Recent research suggests an important role of epigenetics in shaping and maintaining cell identity in the brain. To elucidate the role of DNA methylation in neuronal differentiation, we developed a new protocol for separation of nuclei from the two major populations of human prefrontal cortex neurons--GABAergic interneurons and glutamatergic (GLU) projection neurons. Major differences between the neuronal subtypes were revealed in CpG, non-CpG and hydroxymethylation (hCpG). A dramatically greater number of undermethylated CpG sites in GLU versus GABA neurons were identified. These differences did not directly translate into differences in gene expression and did not stem from the differences in hCpG methylation, as more hCpG methylation was detected in GLU versus GABA neurons. Notably, a comparable number of undermethylated non-CpG sites were identified in GLU and GABA neurons, and non-CpG methylation was a better predictor of subtype-specific gene expression compared to CpG methylation. Regions that are differentially methylated in GABA and GLU neurons were significantly enriched for schizophrenia risk loci. Collectively, our findings suggest that functional differences between neuronal subtypes are linked to their epigenetic specification.
authors.affiliation: James J. Peters VA Medical Center, Bronx, NY 10468, USA The Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Kozlenkov
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Minghui
authors.initials: M
authors.lastname: Wang
authors.affiliation: James J. Peters VA Medical Center, Bronx, NY 10468, USA The Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Panos
authors.initials: P
authors.lastname: Roussos
authors.affiliation: Hospital for Special Surgery, New York, NY 10021, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Rudchenko
authors.affiliation: Hospital for Special Surgery, New York, NY 10021, USA.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Barbu
authors.affiliation: Illumina, Inc., San Diego, CA 92122, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Bibikova
authors.affiliation: Illumina, Inc., San Diego, CA 92122, USA.
authors.forename: Brandy
authors.initials: B
authors.lastname: Klotzle
authors.affiliation: Department of Psychiatry, Columbia University, New York, NY 10032, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dwork
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: The Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Yasmin L
authors.initials: YL
authors.lastname: Hurd
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
authors.forename: Eugene V
authors.initials: EV
authors.lastname: Koonin
authors.affiliation: Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0002-4586-3294
authors.initials: M
authors.lastname: Wegner
authors.affiliation: James J. Peters VA Medical Center, Bronx, NY 10468, USA The Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Stella.Dracheva@mssm.edu.
authors.forename: Stella
authors.initials: S
authors.lastname: Dracheva
mesh_terms: D000328:Adult; D001344:Autopsy; D001931:Brain Mapping; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D059330:GABAergic Neurons / Q000166:cytology / Q000378:metabolism*; D056426:Genetic Loci; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008297:Male; D008867:Microtomy; D008875:Middle Aged; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009928:Organ Specificity; D017397:Prefrontal Cortex / Q000033:anatomy & histology / Q000378:metabolism*; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D018698:Glutamic Acid