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. 2016 Sep 30:7:1496.
doi: 10.3389/fpsyg.2016.01496. eCollection 2016.

Epigenetics in Schizophrenia: A Pilot Study of Global DNA Methylation in Different Brain Regions Associated with Higher Cognitive Functions

Raúl Alelú-Paz  1 , Francisco J Carmona  2 , José V Sanchez-Mut  2 , Ariel Cariaga-Martínez  3 , Ana González-Corpas  4 , Nadia Ashour  4 , Maria J Orea  4 , Ana Escanilla  5 , Alfonso Monje  5 , Carmen Guerrero Márquez  6 , Jerónimo Saiz-Ruiz  7 , Manel Esteller  8 , Santiago Ropero  4
Affiliations

Epigenetics in Schizophrenia: A Pilot Study of Global DNA Methylation in Different Brain Regions Associated with Higher Cognitive Functions

Raúl Alelú-Paz et al. Front Psychol. .

Abstract

Attempts to discover genes that are involved in the pathogenesis of major psychiatric disorders have been frustrating and often fruitless. Concern is building about the need to understand the complex ways in which nature and nurture interact to produce mental illness. We analyze the epigenome in several brain regions from schizophrenic patients with severe cognitive impairment using high-resolution (450K) DNA methylation array. We identified 139 differentially methylated CpG sites included in known and novel candidate genes sequences as well as in and intergenic sequences which functions remain unknown. We found that altered DNA methylation is not restricted to a particular region, but includes others such as CpG shelves and gene bodies, indicating the presence of different DNA methylation signatures depending on the brain area analyzed. Our findings suggest that epimutations are not relatables between different tissues or even between tissues' regions, highlighting the need to adequately study brain samples to obtain reliable data concerning the epigenetics of schizophrenia.

Keywords: DNA methylation; cognition; epigenetics; executive function; human brain; memory; psychology; schizophrenia.

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Figures

Figure 1
Figure 1
(A) Total number of hyper and hypomethylated CpG sites both in schizophrenic and healthy samples; (B) Hierarchical cluster analysis of 301 probes in the total samples included in our study with a 0.20-fold change in β-values as the cut-off (SD < 30%; Green, samples with lowest methylation level; Red, samples with highest methylation level). Cluster analysis discriminated between schizophrenic patients (orange box) and control samples (blue box); (C,D,E) Representative example of the scatter plot for CpG methylation values (AVGβ) between healthy and schizophrenic samples in the (A) DLPC (R2 = 0.9945); (B) Hippocampus (R2 = 0.9949); and (C) ACC (R2 = 0.9931).
Figure 2
Figure 2
(A) Functional genomic distribution, (B) CpG content and neighborhood context, and (C) associated RNA transcripts of the 66 differentially methylated CpGs between schizophrenic and healthy samples in the DLPC; (D) Network analysis using STRING (V9.05) identified different protein-protein associations. Stronger associations are represented by thicker lines.
Figure 3
Figure 3
(A) Functional genomic distribution, (B) CpG content and neighborhood context, and (C) associated RNA transcripts of the 18 differentially methylated CpGs between schizophrenic and healthy samples in the hippocampus; (D) Network analysis (STRING V9.05).
Figure 4
Figure 4
(A) Functional genomic distribution, (B) CpG content and neighborhood context, and (C) associated RNA transcripts of the 55 differentially methylated CpGs between schizophrenic and healthy samples in the ACC; (D) Network analysis in the ACC.
See this image and copyright information in PMC

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