Mild expression differences of MECP2 influencing aggressive social behavior

• Published in: EMBO molecular medicine 2014-05, Vol.6 (5), p.662-684
• Main 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
• Format: Article
• Language: English
• Subjects: Aggression; Animals; Cohort Studies; EMBO16; EMBO27; Gene Expression Profiling; Genetic Association Studies; genetic background; Genetic Predisposition to Disease; human; Humans; Leukocytes, Mononuclear; Methyl-CpG-Binding Protein 2 - biosynthesis; Mice, Inbred C57BL; microRNA; MicroRNAs - metabolism; mouse; phenotype‐based genetic association study; Polymorphism, Single Nucleotide; Research Article
• ISSN: 1757-4676; 1757-4684
• DOI: 10.1002/emmm.201303744

The X‐chromosomal MECP2/Mecp2 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 Mecp2 enhances aggression. Surprisingly, when the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This suggests that Mecp2 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 MECP2 SNPs rs2239464 (G/A) and rs2734647 (C/T; 3′UTR) associated with aggression, with the G and C carriers, respectively, being more aggressive. This finding was replicated in an independent schizophrenia cohort. Allele‐specific MECP2 mRNA expression differs in peripheral blood mononuclear cells by ~50% (rs2734647: C > T). Notably, the brain‐expressed, species‐conserved miR‐511 binds to MECP2 3′UTR only in T carriers, thereby suppressing gene expression. To conclude, subtle MECP2/Mecp2 expression alterations impact aggression. While the mouse data provides evidence of an interaction between genetic background and mild Mecp2 over expression, the human data convey means by which genetic variation affects MECP2 expression and behavior. Synopsis The transcriptional regulator MECP2 is known to affect neurodevelopment. This study associates aggressive social behavior with MECP2 genotype and expression changes in both male schizophrenic patients and mouse models of different genetic background. Mild (50%) overexpression of Mecp2 in mice influences male social aggression. The genetic background (FVB/N versus C57Bl/6N) modulates this overexpression‐associated phenotype. Normal genetic variation of MECP2 (single nucleotide polymorphisms) co‐determines the level of aggression in two independent cohorts of schizophrenic men. miR‐511 downregulates MECP2 expression in T but not C carriers of SNP rs2734647, suggesting miR‐511 targeted therapies in MECP2 gene duplication syndrome. Graphical Abstract The transcriptional regulator MECP2 is known to affect neurodevelopment. This study associates aggressive social behavior with MECP2 genotype and expression changes in both male schizophrenic patients and mouse models of different genetic background.