title: Rebalancing gene haploinsufficiency in vivo by targeting chromatin.
abstract: Congenital heart disease (CHD) affects eight out of 1,000 live births and is a major social and health-care burden. A common genetic cause of CHD is the 22q11.2 deletion, which is the basis of the homonymous deletion syndrome (22q11.2DS), also known as DiGeorge syndrome. Most of its clinical spectrum is caused by haploinsufficiency of Tbx1, a gene encoding a T-box transcription factor. Here we show that Tbx1 positively regulates monomethylation of histone 3 lysine 4 (H3K4me1) through interaction with and recruitment of histone methyltransferases. Treatment of cells with tranylcypromine (TCP), an inhibitor of histone demethylases, rebalances the loss of H3K4me1 and rescues the expression of approximately one-third of the genes dysregulated by Tbx1 suppression. In Tbx1 mouse mutants, TCP treatment ameliorates substantially the cardiovascular phenotype. These data suggest that epigenetic drugs may represent a potential therapeutic strategy for rescue of gene haploinsufficiency phenotypes, including structural defects.
authors.affiliation: CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso, Via Pietro Castellino 111, Naples 80131, Italy.
authors.forename: Filomena Gabriella
authors.initials: FG
authors.lastname: Fulcoli
authors.affiliation: Istituto per le Applicazioni del Calcolo, CNR, Naples, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Franzese
authors.affiliation: Shanghai Pediatric Congenital Heart Institute, Institute for Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China.
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Shanghai Pediatric Congenital Heart Institute, Institute for Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Istituto per le Applicazioni del Calcolo, CNR, Naples, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Angelini
authors.affiliation: CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso, Via Pietro Castellino 111, Naples 80131, Italy.|Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples 80131, Italy.
authors.forename: Antonio
authors.identifier: 0000-0002-5330-0256
authors.initials: A
authors.lastname: Baldini
mesh_terms: D000818:Animals; D002843:Chromatin; D004062:DiGeorge Syndrome / Q000235:genetics* / Q000628:therapy; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D057895:Haploinsufficiency / Q000187:drug effects* / Q000235:genetics; D042421:Histone Code / Q000235:genetics*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors*; D051379:Mice; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009154:Mutation; D020825:T-Box Domain Proteins / Q000235:genetics*; D014191:Tranylcypromine / Q000494:pharmacology*
chemical_list: D002843:Chromatin; D008996:Monoamine Oxidase Inhibitors; D020825:T-Box Domain Proteins; C108625:TBX1 protein, human; C491573:Tbx1 protein, mouse; D014191:Tranylcypromine; D056466:Histone Demethylases