A cell epigenotype specific model for the correction of brain cellular heterogeneity bias and its application to age, brain region and major depression

Jerry Guintivano, Martin J. Aryee, Zachary A. Kaminsky

Research output: Contribution to journalArticlepeer-review

Abstract

Brain cellular heterogeneity may bias DNA methylation patterns, influencing findings in psychiatric epigenetic studies. We performed fluorescence activated cell sorting (FACS) of neuronal nuclei and Illumina HM450 DNA methylation profiling in post mortem frontal cortex of 29 major depression subjects and 29 matched controls. We identify genomic features and ontologies enriched for cell type specific epigenetic variation. Using the top cell epigenotype specific (CETS) marks, we generated a publically available R package, "CETS," located at http://psychiatry.igm.jhmi.edu/kaminsky/software.htm that is capable of quantifying neuronal proportions and generating in silico neuronal profiles capable of removing cell type heterogeneity bias from DNA methylation data. We demonstrate a significant overlap in major depression DNA methylation associations between FACS separated and CETS model generated neuronal profiles relative to bulk profiles. CETS derived neuronal proportions correlated significantly with age in the frontal cortex and cerebellum and accounted for epigenetic variation between brain regions. CETS based control of cellular heterogeneity will enable more robust hypothesis testing in the brain.

Original languageEnglish (US)
Pages (from-to)290-302
Number of pages13
JournalEpigenetics
Volume8
Issue number3
DOIs
StatePublished - Mar 2013

Keywords

  • Age
  • Brain region
  • Cellular heterogeneity
  • DNA methylation
  • Epigenetics
  • Fluorescence activated cell sorting
  • Glia
  • Microarray
  • Neurons

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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