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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, Cedric and Harvey, Richard P. 2015, NKX2-5 mutations causative for congenital heart disease retain functionality and are directed to hundreds of targets, eLife, vol. 4, pp. 1-30, doi: 10.7554/eLife.06942.

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Title NKX2-5 mutations causative for congenital heart disease retain functionality and are directed to hundreds of targets
Author(s) 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, Cedric
Harvey, Richard P.
Journal name eLife
Volume number 4
Start page 1
End page 30
Total pages 30
Publisher eLife Sciences Publications
Place of publication Cambridge, United Kingdom
Publication date 2015-07-06
ISSN 2050-084X
Summary 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 transformationspecific (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 gainof- function in congenital heart disease.
Language eng
DOI 10.7554/eLife.06942
Field of Research 110201 Cardiology (incl Cardiovascular Diseases)
Socio Economic Objective 920103 Cardiovascular System and Diseases
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2015, The Authors
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30081458

Document type: Journal Article
Collections: School of Medicine
Open Access Collection
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Created: Thu, 18 Feb 2016, 07:59:01 EST

Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.