TY - JOUR TI - NKX2-5 mutations causative for congenital heart disease retain functionality and are directed to hundreds of targets AU - Bouveret, Romaric AU - Waardenberg, Ashley J AU - Schonrock, Nicole AU - Ramialison, Mirana AU - Doan, Tram AU - de Jong, Danielle AU - Bondue, Antoine AU - Kaur, Gurpreet AU - Mohamed, Stephanie AU - Fonoudi, Hananeh AU - Chen, Chiann-mun AU - Wouters, Merridee A AU - Bhattacharya, Shoumo AU - Plachta, Nicolas AU - Dunwoodie, Sally L AU - Chapman, Gavin AU - Blanpain, Cédric AU - Harvey, Richard P A2 - Buckingham, Margaret VL - 4 PY - 2015 DA - 2015/07/06 SP - e06942 C1 - eLife 2015;4:e06942 DO - 10.7554/eLife.06942 UR - https://doi.org/10.7554/eLife.06942 AB - 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. KW - cardiogenesis KW - transcription factor KW - genetic disease JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -