NKX2-5 mutations causative for congenital heart disease retain functionality and are directed to hundreds of targets

Romaric Bouveret, Ashley J Waardenberg, Nicole Schonrock, Mirana Soa Manarivo Ramialison, Tram B Doan, Danielle de Jong, Antoine Bondue, Gurpreet Kaur, Stephanie Mohamed, Hananeh Fonoudi, Chiann-mun Chen, Merridee A Wouters, Shoumo Bhattacharya, Nicolas Daniel Plachta, Sally L Dunwoodie, Gavin Chapman, Cedric Blanpain, Richard P Harvey

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53 Citations (Scopus)


To model cardiac gene regulatory networks in health and disease we used DamID to establish robust target gene sets for the cardiac homeodomain factor NKX2-5 and two congenital heart disease-associated mutants carrying a crippled homeodomain, which normally functions as DNA- and protein-binding interface. Despite compromised direct DNA-binding, NKX2-5 mutants retained partial functionality and bound hundreds of targets, including NKX2-5 wild type targets and unique sets of off-targets . NKX2-5HD, which lacks the entire homeodomain, could still dimerise with wild type NKX2-5 and its cofactors, including newly-discovered cofactors of the ETS family, through the conserved tyrosine-rich domain (YRD). NKX2-5HD off-targets showed overrepresentation of many binding motifs, including ETS motifs, the majority co-occupied by ETS proteins as determined by DamID. Off-targets of an NKX2-5 YRD mutant were not enriched in ETS targets. Our study reveals off-target binding and transcriptional activity for NKX2-5 mutations driven in part by cofactor interactions, suggesting a novel type of gain-of-function in congenital heart disease.
Original languageEnglish
Article numbere06942
Number of pages30
Publication statusPublished - 2015

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