The DNA methylome and transcriptome of different brain regions in schizophrenia and bipolar disorder.
Extensive changes in DNA methylation have been observed in schizophrenia (SC) and bipolar disorder (BP), and may contribute to the pathogenesis of these disorders. Here, we performed genome-scale DNA methylation profiling using methylated DNA immunoprecipitation followed by sequencing (MeDIP-seq) on two brain regions (including frontal cortex and anterior cingulate) in 5 SC, 7 BP and 6 normal subjects. Comparing with normal controls, we identified substantial differentially methylated regions (DMRs) in these two brain regions of SC and BP. To our surprise, different brain regions show completely distinct distributions of DMRs across the genomes. In frontal cortex of both SC and BP subjects, we observed widespread hypomethylation as compared to normal controls, preferentially targeting the terminal ends of the chromosomes. In contrast, in anterior cingulate, both SC and BP subjects displayed extensive gain of methylation. Notably, in these two brain regions of SC and BP, only a few DMRs overlapped with promoters, whereas a greater proportion occurs in introns and intergenic regions. Functional enrichment analysis indicated that important psychiatric disorder-related biological processes such as neuron development, differentiation and projection may be altered by epigenetic changes located in the intronic regions. Transcriptome analysis revealed consistent dysfunctional processes with those determined by DMRs. Furthermore, DMRs in the same brain regions from SC and BP could successfully distinguish BP and/or SC from normal controls while differentially expressed genes could not. Overall, our results support a major role for brain-region-dependent aberrant DNA methylation in the pathogenesis of these two disorders.
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China.
Yun
Y
Xiao
The Center of Excellence in Neuroscience, Texas Tech University Health Science Center, El Paso, Texas, United States of America.
Cynthia
C
Camarillo
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China.
Yanyan
Y
Ping
Departments of Psychiatry, Texas Tech University Health Science Center, El Paso, Texas, United States of America.
Tania Bedard
TB
Arana
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China.
Hongying
H
Zhao
Southwest Brain Bank, Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
Peter M
PM
Thompson
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China.
Chaohan
C
Xu
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China.
Bin Brenda
BB
Su
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China.
Huihui
H
Fan
The Center of Excellence in Neuroscience, Texas Tech University Health Science Center, El Paso, Texas, United States of America.
Javier
J
Ordonez
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China.
Li
L
Wang
University of Toronto, Toronto, Canada.
Chunxiang
C
Mao
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China.
Yunpeng
Y
Zhang
Southwest Brain Bank, Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
Dianne
D
Cruz
Departments of Psychiatry, Texas Tech University Health Science Center, El Paso, Texas, United States of America; The Center of Excellence in Neuroscience, Texas Tech University Health Science Center, El Paso, Texas, United States of America.
Michael A
MA
Escamilla
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China.
Xia
X
Li
Departments of Psychiatry, Texas Tech University Health Science Center, El Paso, Texas, United States of America; College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China; The Center of Excellence in Neuroscience, Texas Tech University Health Science Center, El Paso, Texas, United States of America.
Chun
C
Xu
D001714:Bipolar Disorder / Q000235:genetics*; D001921:Brain / Q000378:metabolism*; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008297:Male; D009928:Organ Specificity; D012559:Schizophrenia / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D059467:Transcriptome