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Title: | NKX2-5 mutations causative for congenital heart disease retain functionality and are directed to hundreds of targets. | Austin Authors: | Bouveret, Romaric;Waardenberg, Ashley J;Schonrock, Nicole;Ramialison, Mirana;Doan, Tram;de Jong, Danielle;Bondue, Antoine;Kaur, Gurpreet;Mohamed, Stephanie;Fonoudi, Hananeh;Chen, Chiann-Mun;Wouters, Merridee A;Bhattacharya, Shoumo;Plachta, Nicolas;Dunwoodie, Sally L;Chapman, Gavin;Blanpain, Cédric;Harvey, Richard P | Affiliation: | Bioinformatics, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia Department of Cardiovascular Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom European Molecular Biology Laboratory, Australian Regenerative Medicine Institute, Monash University, Clayton, Australia Victor Chang Cardiac Research Institute, Darlinghurst, Australia Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium |
Issue Date: | 6-Jul-2015 | metadata.dc.date: | 2015 | Publication information: | eLife 2015; 4: e06942 | Abstract: | We take a functional genomics approach to congenital heart disease mechanism. We used DamID to establish a robust set of target genes for NKX2-5 wild type and disease associated NKX2-5 mutations to model loss-of-function in gene regulatory networks. NKX2-5 mutants, including those with a crippled homeodomain, bound hundreds of targets including NKX2-5 wild type targets and a unique set of "off-targets", and retained partial functionality. NKXΔHD, which lacks the homeodomain completely, could heterodimerize with NKX2-5 wild type and its cofactors, including E26 transformation-specific (ETS) family members, through a tyrosine-rich homophilic interaction domain (YRD). Off-targets of NKX2-5 mutants, but not those of an NKX2-5 YRD mutant, showed overrepresentation of ETS binding sites and were occupied by ETS proteins, as determined by DamID. Analysis of kernel transcription factor and ETS targets show that ETS proteins are highly embedded within the cardiac gene regulatory network. Our study reveals binding and activities of NKX2-5 mutations on WT target and off-targets, guided by interactions with their normal cardiac and general cofactors, and suggest a novel type of gain-of-function in congenital heart disease. | URI: | http://ahro.austin.org.au/austinjspui/handle/1/18646 | DOI: | 10.7554/eLife.06942 | ORCID: | 0000-0002-2121-912X | Journal: | eLife | PubMed URL: | 26146939 | Type: | Journal Article | Subjects: | cardiogenesis developmental biology genetic diseases mouse stem cells transcription factors |
Appears in Collections: | Journal articles |
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