Mild expression differences of MECP2 influencing aggressive social behavior

The X-chromosomal MECP2/Mecp2 gene encodes methyl-CpG-binding protein2, a transcriptional activator and repressor regulating many other genes. Loss-of-function mutations or duplications cause severe neurodevelopmental phenotypes like Rett syndrome. However, the role of common MECP2 polymorphisms for human behavior is unknown. We made the unexpected discovery in FVB/N mice that only mild (~1.5-fold) transgenic overexpression of wildtype Mecp2 induces enhanced aggression while other behavioral domains remain normal. Surprisingly, when the same transgene was expressed in C57BL6/N mice, transgenics showed reduced aggression and social interaction. This suggests that slight expression differences of Mecp2 and its interaction with other modifier genes contribute to behavioral phenotypes, most notably aggression. To test this hypothesis in humans, we performed a phenotype-based genetic association study (PGAS) and took advantage of a database containing detailed phenotypical and genetic data of >1000 schizophrenic subjects. We found that MECP2 SNPs rs2239464 (G/A) and rs2734647 (C/T; 3'UTR) are associated with aggression equivalents (poor impulse control, excitement, uncooperativeness) in males, where we also measured allele-specific mRNA expression differences of ~50% in peripheral blood mononuclear cells. For mechanistic insight, luciferase-reporter assays were performed, testing in silico predicted marker-dependent miRNA binding. As candidate for MECP2 downregulation, hsa-miR-511 was identified and shown to be expressed in aggression-relevant human brain areas. Interestingly, the interaction of both gene products is well conserved in mouse and man. We conclude that subtle MECP2/Mecp2 expression changes impact aggressive social behavior, but we note, based on mouse models, that the genetic background likely contributes a major modifying effect to the resulting phenotype.

Jaar van publicatie:2014

Trefwoorden:MeCP2