Abstract
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.
Highlights
Psychiatric disorders characterized by long-lasting behavioral abnormalities constitute a considerable public health burden [1]
Identification of differentially methylated regions We detected DNA methylation levels for two human brain regions (BA9 and BA24) from 18 individuals composed of five SC, seven bipolar disorder (BP) and six control subjects (Table S1) by MeDIP-seq that uses antibody-based immunoprecipitation of 5-methylcytosine followed by sequencing the immunoprecipitated fractions
In many chromosomes, some local methylation changes in the disorders relative to normal controls were found in the BA9 brain region and interestingly, these local changes tended to occur at the terminal ends of the autosomes (Figure S1C and S1D, and Figure S2)
Summary
Psychiatric disorders characterized by long-lasting behavioral abnormalities constitute a considerable public health burden [1]. Despite the completion of numerous large-scale genome-wide association studies and the recent application of exon sequencing to identify risk loci and structural genomic variants (e.g. copy number variation) associated with these psychiatric disorders, it is becoming clear that the few number of risk genes/loci and extremely rare structural variants are insufficient to account for the risk of psychiatric disorders [2] This is because most psychiatric disorders are associated with molecular abnormalities in multiple genes and signals that control their expression, rather than mere genetic variants in a few genes. The first epigenome-wide study performed by Mill et al [11] comprehensively characterized DNA methylation in the prefrontal cortex of patients with major psychosis by investigating ,27,000 CpG dinucleotides using microarray They identified significant epigenetic changes associated with SC and BP. Dempster et al [12] performed genome-wide analysis of DNA methylation of blood samples from 22 twin pairs discordant for SC and BP using microarray and further demonstrated important DNA methylation changes in the molecular mechanisms associated with SC and BP
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