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

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, and Harvey, Richard P. (2015) NKX2-5 mutations causative for congenital heart disease retain functionality and are directed to hundreds of targets. eLife, 4. e06942.

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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. 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.

Item ID: 55659
Item Type: Article (Research - C1)
ISSN: 2050-084X
Copyright Information: Copyright © 2015, Bouveret et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Funders: National Health and Medical Research Council (NHMRC), Atlantic Philanthropies (AP), British Heart Foundation (BHF), Wellcome Trust (WT), Schweizerische Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Australian Research Council (ARC), European Molecular Biology Organization (EMBO), Human Frontiers in Science Program (HFSP), National Heart Foundation of Australia (NHF)
Projects and Grants: NHMRC 1061539, NHMRC 573732, NHMRC 573703, NHMRC 1052171, NHMRC 514900, NHMRC 1042002, NHMRC 573705, AP 19131, ARC DP0988507, ARC DP120104594, ARC DE120100794, HFSP LT000245/2010-L, HFSP LT00044/2007-L, BHF CH/09/003, WT 083228, EMBO (1133-2009), NHF 1049980, PBEZB-111553
Date Deposited: 27 Sep 2018 23:40
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1114 Paediatrics and Reproductive Medicine > 111401 Foetal Development and Medicine @ 30%
11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110201 Cardiology (incl Cardiovascular Diseases) @ 70%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 100%
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