title: Mild expression differences of MECP2 influencing aggressive social behavior.
abstract: 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 overexpression, the human data convey means by which genetic variation affects MECP2 expression and behavior.
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Martesa
authors.initials: M
authors.lastname: Tantra
authors.forename: Christian
authors.initials: C
authors.lastname: Hammer
authors.forename: Anne
authors.initials: A
authors.lastname: Kästner
authors.forename: Liane
authors.initials: L
authors.lastname: Dahm
authors.forename: Martin
authors.initials: M
authors.lastname: Begemann
authors.forename: Chiranjeevi
authors.initials: C
authors.lastname: Bodda
authors.forename: Kurt
authors.initials: K
authors.lastname: Hammerschmidt
authors.forename: Ina
authors.initials: I
authors.lastname: Giegling
authors.forename: Beata
authors.initials: B
authors.lastname: Stepniak
authors.forename: Aracely
authors.initials: A
authors.lastname: Castillo Venzor
authors.forename: Bettina
authors.initials: B
authors.lastname: Konte
authors.forename: Begun
authors.initials: B
authors.lastname: Erbaba
authors.forename: Annette
authors.initials: A
authors.lastname: Hartmann
authors.forename: Asieh
authors.initials: A
authors.lastname: Tarami
authors.forename: Walter
authors.initials: W
authors.lastname: Schulz-Schaeffer
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.forename: Ashraf U
authors.initials: AU
authors.lastname: Mannan
authors.forename: Hannelore
authors.initials: H
authors.lastname: Ehrenreich
mesh_terms: D000374:Aggression; D000818:Animals; D015331:Cohort Studies; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007963:Leukocytes, Mononuclear; D051783:Methyl-CpG-Binding Protein 2 / Q000096:biosynthesis*; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide
chemical_list: C497392:MECP2 protein, human; C578471:MIRN511 microRNA, human; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D035683:MicroRNAs