Rebalancing gene haploinsufficiency in vivo by targeting chromatin

Filomena Gabriella Fulcoli, Monica Franzese, Xiangyang Liu, Zhen Zhang (), Claudia Angelini () and Antonio Baldini ()
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Filomena Gabriella Fulcoli: CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso
Monica Franzese: Istituto per le Applicazioni del Calcolo, CNR
Xiangyang Liu: Shanghai Pediatric Congenital Heart Institute, Institute for Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine
Zhen Zhang: Shanghai Pediatric Congenital Heart Institute, Institute for Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine
Claudia Angelini: Istituto per le Applicazioni del Calcolo, CNR
Antonio Baldini: CNR Institute of Genetics and Biophysics Adriano Buzzati Traverso

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11688

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