DNA hypomethylation of Synapsin II CpG islands associates with increased gene expression in bipolar disorder and major depression.

Cristiana Cruceanu,Gustavo Turecki,Juan Pablo Lopez,Elena Kutsarova,Corina Nagy,Martin Alda,Elizabeth S Chen,Guy A Rouleau,David R Checknita

doi:10.1186/s12888-016-0989-0

Abstract

BackgroundThe Synapsins (SYN1, SYN2, and SYN3) are important players in the adult brain, given their involvement in synaptic transmission and plasticity, as well as in the developing brain through roles in axon outgrowth and synaptogenesis. We and others previously reported gene expression dysregulation, both as increases and decreases, of Synapsins in mood disorders, but little is known about the regulatory mechanisms leading to these differences. Thus, we proposed to study DNA methylation at theses genes’ promoter regions, under the assumption that altered epigenetic marks at key regulatory sites would be the cause of gene expression changes and thus part of the mood disorder etiology.MethodsWe performed CpG methylation mapping focusing on the three genes’ predicted CpG islands using the Sequenom EpiTYPER platform. DNA extracted from post-mortem brain tissue (BA10) from individuals who had lived with bipolar disorder (BD), major depressive disorder (MDD), as well as psychiatrically healthy individuals was used. Differences in methylation across all CpGs within a CpG island and between the three diagnostic groups were assessed by 2-way mixed model analyses of variance.ResultsWe found no significant results for SYN1 or SYN3, but there was a significant group difference in SYN2 methylation, as well as an overall pattern of hypomethylation across the CpG island. Furthermore, we found a significant inverse correlation of DNA methylation with SYN2a mRNA expression.ConclusionsThese findings contribute to previous work showing dysregulation of Synapsins, particularly SYN2, in mood disorders and improve our understanding of the regulatory mechanisms that precipitate these changes likely leading to the BD or MDD phenotype.Electronic supplementary materialThe online version of this article (doi:10.1186/s12888-016-0989-0) contains supplementary material, which is available to authorized users.

Highlights

The Synapsins (SYN1, SYN2, and SYN3) are important players in the adult brain, given their involvement in synaptic transmission and plasticity, as well as in the developing brain through roles in axon outgrowth and synaptogenesis
To date there is no evidence of altered DNA methylation of these genes in mood disorders; only one study of a single schizophrenia patient suggests potentially variably methylated sites in the distal SYN3 promoter [3] and a recent study in rats proposes that early life stress, a precipitant of depressive behavior, leads to SYN1 transcription start site hypermethylation and related mRNA downregulation in the amygdala [4]
In this study we explored the role of DNA methylation at promoter-region CpG islands mapping to the three synapsin genes: SYN1, SYN2, and SYN3

Summary

Introduction

The Synapsins (SYN1, SYN2, and SYN3) are important players in the adult brain, given their involvement in synaptic transmission and plasticity, as well as in the developing brain through roles in axon outgrowth and synaptogenesis. We proposed to study DNA methylation at theses genes’ promoter regions, under the assumption that altered epigenetic marks at key regulatory sites would be the cause of gene expression changes and part of the mood disorder etiology. Synapsin genes – Synapsin I (SYN1), Synapsin II (SYN2), and Synapsin III (SYN3) – are interesting candidates for the etiology of mood disorders due to their involvement in the adult brain in synaptic transmission and plasticity, as well as in brain development in axon outgrowth and Though the literature provides ample evidence for genetic associations and gene expression increases of Synapsins in mood disorders, little has been done to Cruceanu et al BMC Psychiatry (2016) 16:286 elucidate the regulatory mechanisms that lead to these disturbances. DNA methylation at CpG islands has been most commonly associated to expression regulation – we chose to focus on in silico predicted islands at the proximal promoters of SYN1 (845 bp) and SYN2 (975 bp), as well as at a distal promoter of SYN3 (613 bp) [2]

Objectives

Methods

Results

Conclusion