Journal
ELIFE
Volume 4, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.06942
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Categories
Funding
- National Health and Medical Research Council (NHMRC) [1061539, 573732, 573703, 1052171, 514900, 1042002, 573705]
- Atlantic Philanthropies [19131]
- British Heart Foundation [CH/09/003]
- Wellcome Trust [083228]
- Schweizerische Nationalfonds zur Forderung der Wissenschaftlichen Forschung [PBEZB-111553]
- Australian Research Council (ARC) [DP0988507, DP120104594, DE120100794]
- European Molecular Biology Organization (EMBO) [1133-2009]
- Human Frontier Science Program (HFSP) [LT00044/2007-L, LT000245/2010-L]
- National Heart Foundation of Australia [1049980]
- National Health and Medical Research Council of Australia [1061539] Funding Source: NHMRC
- Australian Research Council [DE120100794, DP0988507] Funding Source: Australian Research Council
- British Heart Foundation [RG/10/17/28553] Funding Source: researchfish
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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. NKX Delta HD, 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. DOI: 10.7554/eLife.06942.001
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