Retinoic acid (RA) and 2,3,7,8-tetrachlorodibenzo-p-dioxin activate distinct ligand-dependent transcription factors, and both cause cardiac malformation and heart failure in zebrafish embryos. We hypothesized that they cause this response by hyperactivating a common set of genes critical for heart development. To test this, we used microarrays to measure transcripts changes in hearts isolated from zebrafish embryos 1,2,4 and 12 h after exposure to 1M RA. We used hierarchical clustering to compare the transcriptional responses produced in the embryonic heart by RA and TCDD. We could identify no early responses in common between the two agents. However, at 12 h both treatments produced a dramatic downregulation of a common cluster of cell cycle progression genes, which we term the Cell Cycle Gene Cluster (CCGC). This was associated with a halt in heart growth. These results suggest that RA and TCDD ultimately trigger a common transcriptional response associated with heart failure, but not through the direct activation of a common set of genes. Among the genes rapidly induced by RA was Nr2F5, a member of the COUP-TF family of transcription repressors. We found that induction of Nr2F5 was both necessary and sufficient for the cardiotoxic response to RA.
Comparative genomics identifies genes mediating cardiotoxicity in the embryonic zebrafish heart.
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View SamplesThe purpose of this experiment is to understand which transcripts are differentially expressed following exposure to TCDD.
TCDD inhibits heart regeneration in adult zebrafish.
Treatment
View SamplesBalanced immune responses in airways of patients with asthma are crucial to succesful clearance of viral infection and proper asthma control.
Rhinovirus-induced epithelial RIG-I inflammasome suppresses antiviral immunity and promotes inflammation in asthma and COVID-19.
Subject, Time
View SamplesWe used an in vitro cardiomyocyte differentiation system with inducible Hey1 or Hey2 expression to study target gene regulation in cardiomyocytes (CM) generated from murine embryonic stem cells (ESC). The effects of Hey1 and Hey2 are largely redundant, but cell type specific. The number of regulated genes is comparable between ESC and CM, but the total number of binding sites is much higher, especially in ESC, targeting mainly genes involved in transcriptional regulation and developmental processes. Repression by Hey generally correlates with the extent of Hey-binding to target promoters, subsequent Hdac recruitment and lower histone acetylation. Functionally, treatment with the Hdac inhibitor TSA abolished Hey target gene regulation. However, in CM the repressive effect of Hey-binding is lost for a subset of genes. These lack Hey-dependent histone deacetylation in CM and are enriched for binding sites of cardiac specific activators like Srf, Nkx2-5, and Gata4.
Mechanisms of epigenetic and cell-type specific regulation of Hey target genes in ES cells and cardiomyocytes.
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View SamplesL-3,4-dihydroxyphenylalanine (levodopa) treatment is the major pharmacotherapy for Parkinson's disease. However, almost all patients receiving levodopa eventually develop debilitating involuntary movements (dyskinesia). While it is known that striatal spiny projection neurons (SPNs) are involved in the genesis of this movement disorder, the molecular basis of dyskinesia is not understood. In this study, we identify distinct cell-type-specific gene expression changes that occur in sub-classes of SPNs upon induction of a parkinsonian lesion followed by chronic levodopa treatment. We identify several hundred genes whose expression is correlated with levodopa dose, many of which are under the control of AP-1 and ERK signaling. In spite of homeostatic adaptations involving several signaling modulators, AP-1-dependent gene expression remains highly dysregulated in direct pathway SPNs (dSPNs) upon chronic levodopa treatment. We also discuss which molecular pathways are most likely to dampen abnormal dopaminoceptive signaling in spiny projection neurons, hence providing potential targets for antidyskinetic treatments in Parkinson's disease.
Molecular adaptations of striatal spiny projection neurons during levodopa-induced dyskinesia.
Specimen part, Treatment
View SamplesComparative analysis can provide important insights into complex biological systems. As demonstrated in the accompanying paper, Translating Ribosome Affinity Purification (TRAP), permits comprehensive studies of translated mRNAs in genetically defined cell populations following physiological perturbations.
Application of a translational profiling approach for the comparative analysis of CNS cell types.
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View SamplesThe cellular heterogeneity of the brain confounds efforts to elucidate the biological properties of distinct neuronal populations.
A translational profiling approach for the molecular characterization of CNS cell types.
No sample metadata fields
View SamplesThe cellular heterogeneity of the brain confounds efforts to elucidate the biological properties of distinct neuronal populations.
A translational profiling approach for the molecular characterization of CNS cell types.
No sample metadata fields
View SamplesThe cellular heterogeneity of the brain confounds efforts to elucidate the biological properties of distinct neuronal populations.
A translational profiling approach for the molecular characterization of CNS cell types.
No sample metadata fields
View SamplesAffymetrix gene expression AID-GFP-positive vs AID-GFP-negative
The B cell mutator AID promotes B lymphoid blast crisis and drug resistance in chronic myeloid leukemia.
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View Samples