Abstract
BackgroundReelin plays a pivotal role in neurodevelopment and in post-natal synaptic plasticity and has been implicated in the pathogenesis of autism spectrum disorder (ASD). The reelin (RELN) gene expression is significantly decreased in ASD, both in the brain and peripherally. Methylation at the RELN gene promoter is largely triggered at puberty, and hypermethylation has been found in post-mortem brains of schizophrenic and bipolar patients.MethodsIn this study, we assessed RELN gene methylation status in post-mortem temporocortical tissue samples (BA41/42 or 22) of six pairs of post-puberal individuals with ASD and typically developing subjects, matched for sex (male:female, M:F = 5:1), age, and post-mortem interval.ResultsASD patients display a significantly higher number of methylated CpG islands and heavier methylation in the 5′ region of the RELN gene promoter, spanning from −458 to −223 bp, whereas controls have more methylated CpG positions and greater extent of methylation at the 3′ promoter region, spanning from −222 to +1 bp. The most upstream promoter region (−458 to −364 bp) is methylated only in ASD brains, while the most downstream region (−131 to +1 bp) is methylated exclusively in control brains. Within this general framework, three different methylation patterns are discernible, each correlated with different extents of reduction in reelin gene expression among ASD individuals compared to controls.ConclusionsThe methylation pattern is different in ASD and control post-mortem brains. ASD-specific CpG positions, located in the most upstream gene promoter region, may exert a functional role potentially conferring ASD risk by blunting RELN gene expression.Electronic supplementary materialThe online version of this article (doi:10.1186/s11689-016-9151-z) contains supplementary material, which is available to authorized users.
Highlights
Reelin plays a pivotal role in neurodevelopment and in post-natal synaptic plasticity and has been implicated in the pathogenesis of autism spectrum disorder (ASD)
Differential methylation at the RELN gene promoter between ASD and control brains ASD and control brains collectively display methylation at 24 different CpG positions distributed along the RELN gene promoter between −458 and −43 bp (Figs. 1 and 2)
The distribution of methylated CpG positions across the RELN gene promoter is different between ASD and control brains
Summary
Reelin plays a pivotal role in neurodevelopment and in post-natal synaptic plasticity and has been implicated in the pathogenesis of autism spectrum disorder (ASD). Post-natally, reelin is expressed at high levels primarily in the GABAergic interneurons of the cerebral cortex, hippocampus, and olfactory bulb; perhaps even more relevant to ASD, synaptic strength and plasticity are enhanced by reelin signaling upon binding to apoER2 and VLDLR receptors and subsequent activation of NMDA and AMPA receptors [6, 8,9,10]. It exerts a proteolytic activity on extracellular matrix proteins, which is inhibited by organophosphates [11]. These isoforms are conserved across species and may affect RELN gene expression being located at the 3′ end
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