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Series GSE44902 Query DataSets for GSE44902
Status Public on Jul 07, 2015
Title NKX2-5 mutations causative for congenital heart disease retain functionality and are directed to hundreds of targets
Organism Mus musculus
Experiment type Genome binding/occupancy profiling by genome tiling array
Summary NKX2-5 is a homeodomain transcription factor that plays a central role in the cardiac gene regulatory network, and is commonly mutated in human congenital heart disease. Here, we take a functional genomics approach to congenital heart disease mechanism. We used DamID to establish a robust set of target genes for both wild type NKX2-5 and a mutation lacking the homeodomain (NKX2-5delHD), the latter to model loss-of-function in gene regulatory network. NKX2-5delHD bound hundreds of targets including NKX2-5 wild type targets and a unique set of “off-targets”, and retained partial functionality. We showed that NKX2-5delHD could heterodimerize with NKX2-5 wild type and cofactors, including ubiquitous ETS family members ELK1 and ELK4, through a tyrosine-rich homophilic interaction domain (YRD). NKX2-5delHD off-targets, but not those of an NKX2-5 YRD mutant, were enriched in ETS motifs and were occupied by ELK1/ELK4 proteins, as determined by DamID. Our study reveals unexpected activities for NKX2-5 mutations on chromatin, guided by interactions with their normal cardiac and general cofactors, and suggest potential for a novel type of gain-of-function in congenital heart disease.

The supplementary bed file contains all binding regions detected for the N/C-terminal fusions reported in the manuscript, in addition to probe locations, ready to upload directly into UCSC browser (mm9).
 
Overall design DamID-chip TF binding analysis. N and C-terminal Dam fusions to ELK1, ELK4 and SRF vs. Input (dam-only) in HL-1 atrial cardiomyocytes. N-terminal Dam fusions to NKX2-5, NKX2-5YRD^(Y-A) and NKX2-5ΔHD (homeodomain deletion) vs. Input (dam-only) in HL-1 atrial cardiomyocyte.
 
Contributor(s) Bouveret R, Waardenberg AJ, Schonrock N, Ramialison M, Doan T, de Jong D, Bondue A, Kaur G, Mohamed S, Fonoudi H, Chen C, Wouters M, Bhattacharya S, Plachta N, Dunwoodie SL, Chapman G, Blanpain C, Harvey RP
Citation(s) 26146939
Submission date Mar 05, 2013
Last update date Aug 11, 2015
Contact name Ashley Waardenberg
E-mail a.waardenberg@gmail.com
Organization name Children's Medical Research Institute
Lab Waardenberg
Street address 214 Hawkesbury Road
City Westmead
State/province NSW
ZIP/Postal code 2145
Country Australia
 
Platforms (1)
GPL5811 [Mm_PromPR] Affymetrix Mouse Promoter 1.0R Array
Samples (10)
GSM1093630 damELK1
GSM1093631 ELK1dam
GSM1093632 ELK4dam
Relations
BioProject PRJNA192669

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE44902_DamID.bed.gz 375.1 Kb (ftp)(http) BED
GSE44902_RAW.tar 1.2 Gb (http)(custom) TAR (of CEL, COD)
Raw data provided as supplementary file
Processed data provided as supplementary file
Processed data is available on Series record

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