Bouveret, Romaric and Waardenberg, Ashley J and Schonrock, Nicole and Ramialison, Mirana and Doan, Tram and de Jong, Danielle and Bondue, Antoine and Kaur, Gurpreet and Mohamed, Stephanie and Fonoudi, Hananeh and Chen, Chiann-Mun and Wouters, Merridee A and Bhattacharya, Shoumo and Plachta, Nicolas and Dunwoodie, Sally L and Chapman, Gavin and 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. ISSN 2050-084X (OA)
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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.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 21 Jan 2016 21:56 |
| Last Modified: | 28 Sep 2016 05:37 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/210 |
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