Mild expression differences of MECP2 influencing aggressive social behavior

EMBO Molecular Medicine

Martesa Tantra⁴  Christian Hammer⁴  Anne Kästner⁴  Liane Dahm⁴  Martin Begemann⁴  Chiranjeevi Bodda²  Kurt Hammerschmidt⁵  Ina Giegling³  Beata Stepniak⁴  Aracely Castillo Venzor⁴  Bettina Konte³  Begun Erbaba⁴  Annette Hartmann³  Asieh Tarami⁴  Walter Schulz-Schaeffer¹  Dan Rujescu³  Ashraf U Mannan² 

[1] Department of Neuropathology, University Medical Center Göttingen, Göttingen, Germany;DFG Center for Nanoscale Microscopy & Molecular Physiology of the Brain (CNMPB), Göttingen, Germany;Department of Psychiatry, University of Halle, Halle, Germany;Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany;Cognitive Ethology Laboratory, German Primate Center, Halle, Germany

关键词: genetic background;    human;    microRNA;    mouse;    phenotype‐based genetic association study;   

DOI  :  10.1002/emmm.201303744

来源: Wiley

【 摘 要 】

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.

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.

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.