The development of vertebrate extremities is a complex process which requires a highly coordinated network of different transcriptional activities. The homeodomain transcription factor Shox2 is a key player in limb formation controlling neural, muscular and skeletal development.
Tbx4 interacts with the short stature homeobox gene Shox2 in limb development.
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View SamplesThe development of vertebrate extremities is a complex process which requires a highly coordinated network of different transcriptional activities. The homeodomain transcription factor Shox2 is a key player in limb formation controlling neural, muscular and skeletal development. Here, we compared gene expression profiles of wildtype and Shox2 knockout limbs using microarray experiments to identify Shox2 target genes.
Tbx4 interacts with the short stature homeobox gene Shox2 in limb development.
Specimen part
View SamplesStress induces undifferentiated stem cells to differentiate in a way that looks like normal differentiation
Hyperosmolar stress induces global mRNA responses in placental trophoblast stem cells that emulate early post-implantation differentiation.
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View SamplesThe hearts rhythm is initiated and regulated by a group of specialized cells in the sinoatrial node (SAN), the primary pacemaker of the heart. Abnormalities in the development of the SAN can result in irregular heart rates (arrhythmias). Although several of the critical genes important for SAN formation have been identified, our understanding of the transcriptional network controlling SAN development remains at a relatively early stage. The homeodomain transcription factor Shox2 plays an essential early role in the specification and patterning of the SAN.
Islet1 is a direct transcriptional target of the homeodomain transcription factor Shox2 and rescues the Shox2-mediated bradycardia.
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View SamplesDeficiency of the human short stature homeobox-containing gene (SHOX) has been identified in several disorders characterized by reduced height and skeletal anomalies such as Turner, Leri-Weill and Langer syndrome as well as idiopathic short stature. Although highly conserved in vertebrates, rodents lack a SHOX orthologue.
Identification of novel SHOX target genes in the developing limb using a transgenic mouse model.
Specimen part
View SamplesIn progressed puberty, estrogen is responsible for the deceleration of growth by stimulating growth plate maturation. The mechanism of action is largely unknown. We obtained pubertal growth plate specimens of the same girl at Tanner stage B2 and Tanner stage B3, which allowed us to address this issue in more detail. Histological analysis showed that progression of puberty coincided with characteristic morphological changes associated with growth plate maturation, such as decreases in total growth plate height (p=0.002), height of the individual zones (p<0.001) and a increase in intercolumnar space (p<0.001). Microarray analysis of the specimens identified 394 genes (72% upregulated, 28% downregulated) changing with progression of puberty. Overall changes in gene expression were small (average 1.1 fold change). The 394 genes mapped to 13 significantly changing pathways (p<0.05) in majority belonging to extracellular matrix, cell cycle and cell death, which are all related to growth plate maturation. We next scanned the upstream promoter regions of the 394 genes for the presence of evolutionary conserved binding sites for transcription factors implemented in growth plate maturation such as Estrogen Receptor, Androgen Receptor, Elk1, Stat5b, CREBP and Runx2. Runx2 and Elk1, but not estrogen receptor binding sites were enriched and were present in 87 and 43 out of the 394 genes, respectively.In conclusion, our data suggest a role for Runx2 and Elk1 in growth plate maturation and provides suggestive evidence that the effect of estrogen on growth plate maturation is not mediated by activating genomic estrogen signalling in growth plate chondrocytes.
Genome-wide screening in human growth plates during puberty in one patient suggests a role for RUNX2 in epiphyseal maturation.
Sex, Specimen part, Disease
View SamplesWe used human fetal bone marrow-derived mesenchymal stromal cells (hfMSCs) differentiating towards chondrocytes as an alternative model for the human growth plate (GP). Our aims were to study gene expression patterns associated with chondrogenic differentiation to assess whether chondrocytes derived from hfMSCs are a suitable model for studying the development and maturation of the GP. hfMSCs efficiently formed hyaline cartilage in a pellet culture in the presence of TGFB3 and BMP6. Microarray and principal component analysis were applied to study gene expression profiles during chondrogenic differentiation. A set of 232 genes was found to correlate with in vitro cartilage formation. Several identified genes are known to be involved in cartilage formation and validate the robustness of the differentiating hfMSC model. KEGG pathway analysis using the 232 genes revealed 9 significant signaling pathways correlated with cartilage formation. To determine the progression of growth plate cartilage formation, we compared the gene expression profile of differentiating hfMSCs with previously established expression profiles of epiphyseal GP cartilage. As differentiation towards chondrocytes proceeds, hfMSCs gradually obtain a gene expression profile resembling epiphyseal GP cartilage. We visualized the differences in gene expression profiles as protein interaction clusters and identified many protein clusters that are activated during the early chondrogenic differentiation of hfMSCs showing the potential of this system to study GP development. To determine the progression of growth plate cartilage formation, we compared the gene expression profile of differentiating hfMSCs with previously established expression profiles of epiphyseal GP cartilage. As differentiation towards chondrocytes proceeds, hfMSCs gradually obtain a gene expression profile resembling epiphyseal GP cartilage. We visualized the differences in gene expression profiles as protein interaction clusters and identified many protein clusters that are activated during the early chondrogenic differentiation of hfMSCs showing the potential of this system to study GP development.
Fetal mesenchymal stromal cells differentiating towards chondrocytes acquire a gene expression profile resembling human growth plate cartilage.
Specimen part, Time
View SamplesComparison of human prepuberal articular and growth plate cartilage
Gremlin 1, frizzled-related protein, and Dkk-1 are key regulators of human articular cartilage homeostasis.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity.
Specimen part
View SamplesEnzymes catalyzing the methylation of the 5-position of cytosine (mC) have essential roles in regulating gene expression, genome stability, and maintaining cellular identity. Recently Tet1, which is highly expressed in embryonic stem (ES) cells, was found to oxidize the methyl group of mC converting it to 5-hydroxymethyl cytosine (hmC)3. Here, we present the genome-wide mapping of Tet1 and hmC in mouse ES cells. We show that Tet1 binds throughout the genome with the majority of binding sites located at transcription start sites (TSSs) and within genes. Similar to Tet1 and mC, also hmC is found throughout the genome and in particular in gene bodies. However, in contrast to mC, hmC is enriched at TSSs. Tet1 and hmC are associated with genes critical for the control of development and differentiation, which become methylated during differentiation. Surprisingly our results also suggest that Tet1 has a role in transcriptional repression. We show that Tet1 binds to a significant proportion of target genes that are positive for the Polycomb repressive histone mark H3K27me3, and that downregulation of Tet1 also leads to increased expression of a group of Tet1 target genes. In agreement with a potential repressive function, we show that Tet1 associates with the Sin3A co-repressor complex, which also co-localises with Tet1 throughout the genome. We propose that Tet1 fulfils dual functions in transcriptional regulation, where it fine-tunes DNA methylation and associates with the Sin3A co-repressor complex to prevent transcriptional activation.
TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity.
Specimen part
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