Rebalancing gene haploinsufficiency in vivo by targeting chromatin

Here we show that the T-box transcription factor encoded by Tbx1 positively regulates monomethylation of histone 3 lysine 4 (H3K4me1) at a significant number of regions that it occupies throughout the genome, often located at the 3'' end of target genes. Treatment of cells with Tranylcypromine (TCP), an inhibitor of histone demethylases, rescues the expression of approx. one third of the genes dysregulated by Tbx1 suppression and it rebalances H3K4me1 levels at many Tbx1 occupied sites. In addition, TCP treatment of mouse models of the 22q11.2DS ameliorates substantially the cardiovascular phenotype. Overall design: Examination of Tbx1 binding profile, H3K4 monomethylation, H3K27 acetylation and transcription profile in P19Cl6 cells during cariomyocytes differentiation and in mouse embyos.