학술논문
NKX2-5 mutations causative for congenital heart disease retain functionality and are directed to hundreds of targets
Document Type
article
Author
Romaric Bouveret; Ashley J Waardenberg; Nicole Schonrock; Mirana Ramialison; Tram Doan; Danielle de Jong; Antoine Bondue; Gurpreet Kaur; Stephanie Mohamed; Hananeh Fonoudi; Chiann-mun Chen; Merridee A Wouters; Shoumo Bhattacharya; Nicolas Plachta; Sally L Dunwoodie; Gavin Chapman; Cédric Blanpain; Richard P Harvey
Source
eLife, Vol 4 (2015)
Subject
Language
English
ISSN
2050-084X
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.