 |
 |
GEO help: Mouse over screen elements for information. |
|
| 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(s) |
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)
|
|
| Relations |
| BioProject |
PRJNA192669 |
| 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) |
| Processed data provided as supplementary file |
| Processed data are available on Series record |
|
|
|
|
 |
Less...
More...