Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA192669 | ENA |
REPOSITORIES: ENA
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Project description: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).
2015-07-07 | GSE44902 | GEO
Project description:Mutations in Nkx2-5 are a main cause of cardiac congenital heart disease. Here we describe a new Nkx2-5 point-mutation murine model, akin to its human counterpart disease generating mutation. Our model fully reproduces the morphological and physiological clinical presentations of the disease and reveals an under-studied aspect of Nkx2-5 driven pathology, a primary right ventricular dysfunction. We further describe the molecular consequences of disrupting the transcriptional network regulated by Nkx2-5 in the heart and show that Nkx2-5 dependent perturbation of the Wnt signaling pathway promotes heart dysfunction through alteration of cardiomyocyte metabolism. Our data provide mechanistic insights on how Nkx2-5 regulates heart function and metabolism, a novel link in the study of congenital heart disease, and confirms that our models are the first murine genetic models to present all spectra of clinically relevant congenital heart disease phenotypes generated by Nkx2-5 mutations in patients.
2016-12-01 | GSE85902 | GEO
Project description:In the developing heart, heterotypic transcription factors (TFs) interactions, such as between the T-box TF TBX5 and the homeodomain TF NKX2-5 have been proposed as a mechanism for human congenital heart disease. In order to study the role of each TF during heart formation, embryonic stem (ES) cell-derived embryos were generated from KO ES cells for Tbx5, Nkx2-5 or both TFs. We used microarrays to identify changes in the gene expression due to the lack of Tbx5, Nkx2-5 or both TFs during early heart formation. WT, Nkx2-5KO (NKO), Tbx5KO (TKO) and Tbx5KO;Nkx2-5KO (DKO) E8.75 mouse hearts were microdissected for RNA extraction and hybridization on Affymetrix microarrays.
2016-02-11 | E-GEOD-77576 | biostudies-arrayexpress
Project description:In the developing heart, heterotypic transcription factors (TFs) interactions, such as between the T-box TF TBX5 and the homeodomain TF NKX2-5 have been proposed as a mechanism for human congenital heart disease. In order to study the role of each TF during heart formation, embryonic stem (ES) cell-derived embryos were generated from KO ES cells for Tbx5, Nkx2-5 or both TFs. We used microarrays to identify changes in the gene expression due to the lack of Tbx5, Nkx2-5 or both TFs during early heart formation.
2016-02-11 | GSE77576 | GEO
Project description:Dominant mutations in cardiac transcription factor genes cause human inherited congenital heart defects (CHDs), but their molecular basis is not understood. Transcription factors and Brg1/Brm-associated factor (BAF) chromatin remodeling complex interactions suggest potential mechanisms, but the role of BAF complexes in cardiogenesis is not known. Here we show that dosage of Brg1 is critical for mouse and zebrafish cardiogenesis. Disrupting the balance between Brg1 and disease-causing cardiac transcription factors, including Tbx5, Tbx20, and Nkx2-5, causes severe cardiac anomalies, revealing an essential allelic balance between Brg1 and these cardiac transcription factor genes. This suggests that relative levels of transcription factors and BAF complexes are important for heart development, which is supported by reduced occupancy of Brg1 at cardiac genes in Tbx5 haploinsufficient hearts. Our results reveal complex dosage-sensitive interdependence between transcription factors and BAF complexes, providing a potential mechanism underlying transcription factor haploinsufficiency, with implications for multigenic inheritance of CHDs. We performed transcriptional profiling of E11.5 hearts from mice heterozygous for deletions of Brg1, Tbx5, or Nkx2-5, and mice that were compound heterozygotes for Brg1 and each transcription factor gene (Tbx5 and Nkx2-5).
2010-12-22 | E-GEOD-26191 | biostudies-arrayexpress
Project description:The contraction pattern of the heart relies on the activation and conduction of the electrical impulse. Perturbations of cardiac conduction have been associated with congenital and acquired arrhythmias as well as cardiac arrest. The pattern of conduction depends on the regulation of heterogeneous gene expression by key transcription factors and transcriptional enhancers. Here, we assessed the genome-wide occupation of conduction system–regulating transcription factors TBX3, NKX2-5, and GATA4 and of enhancer-associated coactivator p300 in the mouse heart, uncovering cardiac enhancers throughout the genome. Examination of 3 cardiac transcription factors and p300 in adult mouse heart
2012-06-22 | E-GEOD-35151 | biostudies-arrayexpress
Project description:While the heart is the first organ to form during development, the earliest molecular mechanisms surrounding specification and differentiation are not clear. In vertebrates, the first marker of cardiac specification is the expression of the homeobox transcription factor Nkx2-5 and its paralogs. While some downstream targets of Nkx2-5 have been discovered, they alone are not sufficient to completely rescue Nkx2-5 knock-downs, suggesting that other targets of Nkx2-5 regulation remain unknown. In order to identify early targets of Nkx2-5, Xenopus laevis embryos were injected with synthetic Nkx2-5 mRNA and changes in gene expression measured using Affymetrix GeneChips. To interpret the data, X. laevis genomic annotation was augmented using cross-species information from the CrossGene database followed by gene ontology enrichment, network analysis, spatial expression, and Nkx2-5 binding site predictions. This allowed us to compile a list of 99 UniGene clusters representing likely early targets of Nkx2-5. Nkx2-5+GFP or GFP mRNA was injected into 8 cell Xenopus embryos. Total RNA was collected at St. 11.5. comparison of gene expression profiles for treated vs, control
2011-12-01 | E-GEOD-29791 | biostudies-arrayexpress
Project description:Oligogenic inheritance of congenital heart disease involving a NKX2-5 modifier
| PRJNA543244 | ENA
Project description:While the heart is the first organ to form during development, the earliest molecular mechanisms surrounding specification and differentiation are not clear. In vertebrates, the first marker of cardiac specification is the expression of the homeobox transcription factor Nkx2-5 and its paralogs. While some downstream targets of Nkx2-5 have been discovered, they alone are not sufficient to completely rescue Nkx2-5 knock-downs, suggesting that other targets of Nkx2-5 regulation remain unknown. In order to identify early targets of Nkx2-5, Xenopus laevis embryos were injected with synthetic Nkx2-5 mRNA and changes in gene expression measured using Affymetrix GeneChips. To interpret the data, X. laevis genomic annotation was augmented using cross-species information from the CrossGene database followed by gene ontology enrichment, network analysis, spatial expression, and Nkx2-5 binding site predictions. This allowed us to compile a list of 99 UniGene clusters representing likely early targets of Nkx2-5.
2011-12-01 | GSE29791 | GEO
Project description:Oligogenic inheritance of congenital heart disease involving a NKX2-5 modifier [human]
| PRJNA543252 | ENA