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Identification of putative targets of Nkx2-5 in Xenopus laevis using gene expression analysis and cross-species annotation

ABSTRACT: 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.

ORGANISM(S): Xenopus laevis

PROVIDER: GSE29791 | GEO | 2011/12/01

SECONDARY ACCESSION(S): PRJNA155215

REPOSITORIES: GEO

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Identification of putative targets of Nkx2-5 in Xenopus laevis using gene expression analysis and cross-species annotation

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

Identification of putative targets of Nkx2-5 in Xenopus laevis using gene expression analysis and cross-species.

Project description:This SuperSeries is composed of the following subset Series: GSE29791: Identification of putative targets of Nkx2-5 in Xenopus laevis using gene expression analysis and cross-species annotation GSE29795: Gene expression profile for X.laevis embryo head vs.tail Refer to individual Series

2011-12-01 | E-GEOD-29816 | biostudies-arrayexpress

Xenopus laevis

Project description:Identification of putative targets of Nkx2-5 in Xenopus laevis using gene expression analysis and cross-species annotation

| PRJNA155215 | ENA

Identification of putative targets of Nkx2-5 in Xenopus laevis using gene expression analysis and cross-species.

Project description:Identification of putative targets of Nkx2-5 in Xenopus laevis using gene expression analysis and cross-species.

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Project description:Xenopus laevis laevis Transcriptome or Gene expression

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Nkx2-1 Represses a Latent Gastric Differentiation Program in Lung Adenocarcinoma

Project description:Tissue-specific differentiation programs become dysregulated during cancer evolution. The transcription factor Nkx2-1 is a master regulator of pulmonary differentiation that is downregulated in poorly differentiated lung adenocarcinoma. Here we use conditional murine genetics to study the fate of lung epithelial cells upon loss of their master cell fate regulator. Nkx2-1 deletion in normal and neoplastic lung causes not only loss of pulmonary identity but also gastric transdifferentiation. Nkx2-1 maintains pulmonary identity by sequestering the Foxa1 transcription factor at lung-specific loci and by inhibiting Foxa1 binding to gastrointestinal targets. Murine Nkx2-1-negative lung tumors mimic the mucinous subtype of human lung adenocarcinoma, which also exhibits gastric transdifferentiation. Nkx2-1-negative lung adenocarcinomas are dependent on the gastrointestinal gene Hnf4a for efficient initiation. Thus, loss of Nkx2-1 causes transdifferentiation rather than stable dedifferentiation in vivo, suggesting that inactivation of both active and latent differentiation programs are required for tumors to reach a primitive, dedifferentiated state. ChIP-seq data from murine lung adenocarcinomas on (i) transcription factors Nkx2-1 and Foxa in Nkx2-1-deleted tumors and Nkx2-1-positive control tumors, and (ii) four histone marks in Nkx2-1-deleted tumors and Nkx2-1-positive control tumors. (All samples in duplicate and with input controls, i.e. (2 x [(3+3) + (2+8)]) - 1 = 31 samples total - 1 input control used for transcription factor and histone mark, GSM1059357)

2013-04-09 | E-GEOD-43252 | biostudies-arrayexpress

NKX2-5 mutations causative for congenital heart disease retain functionality and are directed to hundreds of targets

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).

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Transcription profiling of mouse Nkx2-5 null cardiomyocytes

Project description:Nkx2-5-GFP+ cells were collected by FACS from whole embryos (E8.0-8.5, 5-12 ps) and dissected heart tubes (E9.0-9.5, 15-21 ps). Because limited numbers of cells were obtained from individual embryos (~300 cells at E8, ~1500 cells at E9.5) mRNA was amplified twice with T7 RNA polymerase and fluorescent cDNA targets were synthesized by the indirect method with either Cy5 or Cy3. Targets from individual Nkx2-5 heterozygous and homozygous null cells were co-hybridized with cDNA probes printed on glass slide microarrays. Two microarray clone sets were used for each hybridization: the NIA/NIH 15,000 clone set derived from mouse non-cardiac embryonic tissue, and a ~6000 cardiac clone set derived in house.

2006-11-27 | E-MEXP-533 | biostudies-arrayexpress

The homeobox transcription factor Nkx2-1 regulates microRNAs controlling downstream gene silencing in lung epithelial cells (mRNA)

Project description:Cell-specific gene expression is achieved by a combination of mechanisms including transcriptional and post-transcriptional regulation. The transcription factor Nkx2-1, essential for lung cell differentiation, mainly acts in transcriptional activation but can directly or indirectly repress gene expression. microRNAs are a class of small non-coding RNA that control one of the major mechanisms of gene repression. To identify miRNAs regulated by Nkx2-1 that may mediate its repressing effects, we knocked-down Nkx2-1 in mouse lung epithelial cell lines and systematically identified targets by genome-wide miR and mRNA expression analyses. Nkx2-1 controls expression of miRs known to contribute to lung cell differentiation in development and disease and others not previously described. Amongst the significantly altered miRs, the mir-106a-363 cluster, miR-1195, miR-378, and miR-346 are directly correlated with the levels of Nkx2-1, whereas miR-200c/b, miR-221, and miR- 222 are inversely correlated. These miRNAs are expressed in embryonic lung at day E11.5, and/or E19.5 determined by in-situ hybridization. Expression of predicted targets of mir-1195, mir-346 and miR-200c and mir-221/222 were evaluated by mRNA expression microarrays in Nkx2-1 knockdown cells identifying those anti-correlated to the corresponding miRNA expression. Genes regulated by mir-1195, Cyp2s1 and Map3k2, by mir-346, Klf6, and miR-200c, Myb, Nfib, and Six1, were validated by qRT-PCR. Inhibition of mir-1195 confirms the inverse correlation of this miRNA with its putative targets Cyp2s1 and Map3k2. This miRNA-mRNA expression analysis identifies potential paths of Nkx2-1 mediated gene repression, and contributes to the understanding of gene regulation in lung epithelial differentiation and development. Nkx2-1 mRNA was knocked down in lung epithelial cells using a lentivirus expressing a shRNA targeting Nkx2-1 (n=3) and compared to empty vector controls (n=3).

2015-12-22 | E-GEOD-47054 | biostudies-arrayexpress

The homeobox transcription factor Nkx2-1 regulates microRNAs controlling downstream gene silencing in lung epithelial cells (microRNA)

2015-12-22 | E-GEOD-47053 | biostudies-arrayexpress