Mild expression differences of MECP2 influencing aggressive social behavior. Issue 5 (20th March 2014)

• Record Type: Journal Article
• Authors: Tantra, Martesa; Hammer, Christian; Kästner, Anne; Dahm, Liane; Begemann, Martin; Bodda, Chiranjeevi; Hammerschmidt, Kurt; Giegling, Ina; Stepniak, Beata; Castillo Venzor, Aracely; Konte, Bettina; Erbaba, Begun; Hartmann, Annette; Tarami, Asieh; Schulz‐Schaeffer, Walter; Rujescu, Dan; Mannan, Ashraf U; Ehrenreich, Hannelore
• Is Part Of: EMBO molecular medicine. Volume 6:Issue 5(2014:May)
• Page Start: 662
• Page End: 684
• Publication Date: 2014-03-20
• Subjects: Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.1002/emmm.201303744
• Languages: English
• ISSNs: 1757-4676

Abstract

<abstract abstract-type="main" id="emmm201303744-abs-0001"> <title>Abstract</title> <p>The X‐chromosomal <italic>MECP2/Mecp2</italic> gene encodes methyl‐CpG‐binding protein 2, a transcriptional activator and repressor regulating many other genes. We discovered in male FVB/N mice that mild (~50%) transgenic overexpression of <italic>Mecp2</italic> enhances aggression. Surprisingly, when the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This suggests that <italic>Mecp2</italic> modulates aggressive social behavior. To test this hypothesis in humans, we performed a phenotype‐based genetic association study (PGAS) in >1000 schizophrenic individuals. We found <italic>MECP2</italic> SNPs rs2239464 (G/A) and rs2734647 (C/T; 3′UTR) associated with aggression, with the G and C carriers, respectively, being <italic>more</italic> aggressive. This finding was replicated in an independent schizophrenia cohort. Allele‐specific <italic>MECP2 </italic>mRNA expression differs in peripheral blood mononuclear cells by ~50% (rs2734647: C > T). Notably, the brain‐expressed, species‐conserved miR‐511 binds to <italic>MECP2</italic> 3′UTR only in T carriers, thereby suppressing gene expression. To conclude, subtle <italic>MECP2/Mecp2</italic> expression alterations impact aggression. While the mouse data provides evidence of an interaction between genetic background and mild <italic>Mecp2 over</italic>expression, the human data convey means by which genetic variation affects <italic>MECP2</italic> expression and behavior.</p> </abstract>