Genome-wide occupancy of CRTC1 in neurons
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE131395 | GEO | 2026/05/27
REPOSITORIES: GEO
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Project description:Mucoepidermoid carcinomas (MEC) is the most common salivary gland malignancy. To date, advanced and nonresectable MEC have poor prognosis and no effective treatment. The CRTC1-MAML2 fusion oncogene, which is associated with more than 50% of MEC, consists of the N-terminal CREB-binding domain of the CREB transcriptional co-activator CRTC1 and the C-terminal transcriptional activation domain of the Notch transcriptional co-activator MAML2. CRTC1-MAML2 fusion was found to interact with CREB and constitutively activate their transcriptional targets. To investigate the genes and pathways regulated by CRTC1-MAML2 fusion oncogene, gene expression profiling analysis were performed in human fusion-positive MEC cells before and after knockdown of both CRTC1-MAML2 and MAML2 as well as in human fusion-negative salivary gland cancer cells before and after MAML2 knockdown only. This study revealed specific transcriptional program induced by the CRTC1-MAML2 fusion oncogene, which potentially mediates CRC1-MAML2 functions in MEC initiation and maintenance. The information will be useful for developing new approaches to block CRTC1-MAML2 fusion-expressing MEC.
2014-04-21 | GSE46580 | GEO
Project description:Mucoepidermoid carcinomas (MEC) is the most common salivary gland malignancy. To date, advanced and nonresectable MEC have poor prognosis and no effective treatment. The CRTC1-MAML2 fusion oncogene, which is associated with more than 50% of MEC, consists of the N-terminal CREB-binding domain of the CREB transcriptional co-activator CRTC1 and the C-terminal transcriptional activation domain of the Notch transcriptional co-activator MAML2. CRTC1-MAML2 fusion was found to interact with CREB and constitutively activate their transcriptional targets. To investigate the genes and pathways regulated by CRTC1-MAML2 fusion oncogene, gene expression profiling analysis were performed in human fusion-positive MEC cells before and after knockdown of both CRTC1-MAML2 and MAML2 as well as in human fusion-negative salivary gland cancer cells before and after MAML2 knockdown only. This study revealed specific transcriptional program induced by the CRTC1-MAML2 fusion oncogene, which potentially mediates CRC1-MAML2 functions in MEC initiation and maintenance. The information will be useful for developing new approaches to block CRTC1-MAML2 fusion-expressing MEC. The fusion-positive H3118 MEC cells were used in this study. The fusion knockdown was performed with two biological replicates for each group. Since we are unable to obtain any shRNA that causes specific knockdown of CRTC1-MAML2, we utilized pSuperRetro-based retroviruses that express shRNA targeting the MAML2 TAD as well as GFP for fusion knock down, and the retroviruses express shRNA targeting luciferase gene (shLuc) and GFP for the control. Cells were infected with retroviruses and cultured for 48 hours. FACS sorting was performed to obtain GFP-positive cells and thus enrich shRNA-expressing cells. RNA was subsequently harvested for microarray analysis. The shMAML2 retroviruses caused the knockdown of MAML2 and CRTC1-MAML2 fusion in fusion-positive H3118 cells.
2014-04-21 | E-GEOD-46580 | biostudies-arrayexpress
Project description:Obesity is described as excessive fat accumulation that drives the development of glucose and lipid metabolism disorders, which is linked to multiple diseases. Crtc1, known as a transducer to regulate Creb activity, plays an important role in several basic physiological functions. Previous studies have shown visible hyperappetite and obesity in Crtc1 knockout (Crtc1-/-) mice. To investigate the effect of Crtc1 on fat accumulation in different organs, we generated Crtc1-/- mice by CRISPR/Cas9 system and regarded Crtc1+/+ as control under the normal feeding conditions. Compared with Crtc1+/+ mice, Crtc1-/- mice exhibited increase of bodyweight which was resulted from the abnormal expansion of white adipocyte. In addition, Crtc1-/- mice were more prone to hyperglycemia and dyslipidemia, supported by the levels of plasma glucose and FABP4. The results of RNA-seq and qRT-PCR in liver and epididymal white adipose tissue (eWAT) showed that the fat accumulation caused by Crtc1 deletion was mainly related to the lipid metabolism of adipose tissue, not liver. Moreover, the up-regulation of lipid metabolism in eWAT induced by Crtc1 deficiency was closely related to the up-regulation of Pparγ signaling pathway. Our findings suggested that endogenous Crtc1 had a protective role in obesity development and Crtc1 deficiency aggravates the progression of fat accumulation and related co-morbidities, which introduced a new insight for treatment of obesity.
2020-09-05 | GSE157270 | GEO
Project description:The adipocyte-derived hormone leptin maintains energy balance by acting on hypothalamic leptin receptors (Leprs) that trigger the signal transducer and activator of transcription 3 (Stat3). Although disruption of Lepr-Stat3 signaling promotes obesity in mice, other features of Lepr function, such as fertility, seem normal, pointing to the involvement of additional regulators. Here we show that the cyclic AMP responsive element–binding protein-1 (Creb1)-regulated transcription coactivator-1 (Crtc1) is required for energy balance and reproduction—Crtc1-/- mice are hyperphagic, obese and infertile. Hypothalamic Crtc1 was phosphorylated and inactive in leptin-deficient ob/ob mice; leptin administration increased amounts of dephosphorylated nuclear Crtc1. Dephosphorylated Crtc1 stimulated expression of the Cartpt and Kiss1 genes, which encode hypothalamic neuropeptides that mediate leptin’s effects on satiety and fertility. Crtc1 overexpression in hypothalamic cells increased Cartpt and Kiss1 gene expression, whereas Crtc1 depletion decreased it. Indeed, leptin enhanced Crtc1 activity over the Cartpt and Kiss1 promoters in cells overexpressing Lepr and these effects were disrupted by expression of a dominant-negative Creb1 polypeptide. As leptin administration increased recruitment of hypothalamic Crtc1 to Cartpt and Kiss1 promoters, our results indicate that the Creb1-Crtc1 pathway mediates the central effects of hormones and nutrients on energy balance and fertility.
2008-09-04 | GSE12209 | GEO
Project description:To identify gene expression changes associated with Crtc1 deficiency, we performed genome-wide transcriptome profile analyses by using mouse cDNA microarrays in the cortex of Crtc1‒/‒ and WT female mice BACKGROUND: Recent studies involve the arginine-decarboxylation product agmatine in mood regulation. Agmatine has antidepressant properties in rodent models of depression, and agmatinase (Agmat), the agmatine-degrading enzyme, is upregulated in the brain of mood disorders patients. We showed that mice lacking CREB-regulated transcription coactivator 1 (CRTC1) associate neurobehavioral and molecular depressive-like endophenotypes, as well as blunted responses to classical antidepressants. METHODS: The molecular basis of the behavioral phenotype of Crtc1‒/‒ mice was further examined using microarray analysis. We characterized Agmat expression in the prefrontal cortex (PFC) and hippocampus (HIP) by quantitative polymerase chain reaction (qPCR), Western blot (WB) analysis, and confocal immunofluorescence microscopy. The antidepressant effect of agmatine was assessed by the forced swim test (FST). Brain-derived neurotrophic factor (BDNF) levels and eukaryotic elongation factor 2 (eEF2) phosphorylation were measured by WB. RESULTS: Microarray, qPCR and WB analyses revealed an upregulation of Agmat in Crtc1‒/‒ PFC and HIP, where immunofluorescence microscopy showed more Agmat-expressing cells, notably parvalbumin- and somatostatin-interneurons. Acute agmatine treatment efficiently improved depressive-like behavior of Crtc1‒/‒ mice in the FST, suggesting that exogenous agmatine has a rapid antidepressant effect through the compensation of agmatine deficit induced by upregulated Agmat. In WT mice, agmatine rapidly increased BDNF levels and eEF2 dephosphorylation, indicating that it might be a fast–acting antidepressant with NMDA receptor antagonist properties. CONCLUSIONS: Collectively, these findings support the involvement of the agmatinergic system in the depressive-like phenotype of Crtc1‒/‒ mice, and allow a better understanding of the agmatinergic system and its putative role in major depression.
2016-07-18 | GSE80633 | GEO
Project description:The adipocyte-derived hormone leptin maintains energy balance by acting on hypothalamic leptin receptors (Leprs) that trigger the signal transducer and activator of transcription 3 (Stat3). Although disruption of Lepr-Stat3 signaling promotes obesity in mice, other features of Lepr function, such as fertility, seem normal, pointing to the involvement of additional regulators. Here we show that the cyclic AMP responsive elementâ??binding protein-1 (Creb1)-regulated transcription coactivator-1 (Crtc1) is required for energy balance and reproductionâ??Crtc1-/- mice are hyperphagic, obese and infertile. Hypothalamic Crtc1 was phosphorylated and inactive in leptin-deficient ob/ob mice; leptin administration increased amounts of dephosphorylated nuclear Crtc1. Dephosphorylated Crtc1 stimulated expression of the Cartpt and Kiss1 genes, which encode hypothalamic neuropeptides that mediate leptinâ??s effects on satiety and fertility. Crtc1 overexpression in hypothalamic cells increased Cartpt and Kiss1 gene expression, whereas Crtc1 depletion decreased it. Indeed, leptin enhanced Crtc1 activity over the Cartpt and Kiss1 promoters in cells overexpressing Lepr and these effects were disrupted by expression of a dominant-negative Creb1 polypeptide. As leptin administration increased recruitment of hypothalamic Crtc1 to Cartpt and Kiss1 promoters, our results indicate that the Creb1-Crtc1 pathway mediates the central effects of hormones and nutrients on energy balance and fertility. Experiment Overall Design: Mice were fasted overnight for 18h and refed for 6h. Hypothalami were obtained from 3 wild-type and 3 Crtc1 knockout mice. Total RNA was isolated from each sample and equal amounts from each sample were pooled for the microarray.
2008-10-25 | E-GEOD-12209 | biostudies-arrayexpress
Project description:To evaluate the genes differentially regulated by CRTC1 in colonic epithelial tumor.
2015-01-01 | GSE59730 | GEO
Project description:Mucoepidermoid carcinomas (MEC) is the most common salivary gland malignancy. To date, advanced and nonresectable MEC have poor prognosis and no effective treatment. The CRTC1-MAML2 fusion oncogene, which is associated with more than 50% of MEC, consists of the N-terminal CREB-binding domain of the CREB transcriptional co-activator CRTC1 and the C-terminal transcriptional activation domain of the Notch transcriptional co-activator MAML2. CRTC1-MAML2 fusion was found to interact with CREB and constitutively activate their transcriptional targets. To investigate the genes and pathways regulated by CRTC1-MAML2 fusion oncogene, gene expression profiling analysis were performed in human fusion-positive MEC cells before and after knockdown of both CRTC1-MAML2 and MAML2 as well as in human fusion-negative salivary gland cancer cells before and after MAML2 knockdown only. This study revealed specific transcriptional program induced by the CRTC1-MAML2 fusion oncogene, which potentially mediates CRC1-MAML2 functions in MEC initiation and maintenance. The information will be useful for developing new approaches to block CRTC1-MAML2 fusion-expressing MEC.
2015-10-30 | GSE57022 | GEO
Project description:Mucoepidermoid carcinomas (MEC) is the most common salivary gland malignancy. To date, advanced and nonresectable MEC have poor prognosis and no effective treatment. The CRTC1-MAML2 fusion oncogene, which is associated with more than 50% of MEC, consists of the N-terminal CREB-binding domain of the CREB transcriptional co-activator CRTC1 and the C-terminal transcriptional activation domain of the Notch transcriptional co-activator MAML2. CRTC1-MAML2 fusion was found to interact with CREB and constitutively activate their transcriptional targets. To investigate the contribution of the transcription factor CREB to mediate the fusion target gene expression, gene expression profiling analysis were performed in two salivary gland tumor cell lines (including fusion-positive H3118 MEC cells and fusion-negative HSY parotid adenocarcinoma cells) before and after CREB knockdown. This study demonstrated that CRTC1-MAML2 co-activation of CREB is a major mechanism underlying CRTC1-MAML2-mediated transcriptional regulation.
2015-10-30 | GSE49673 | GEO
Project description:To evaluate the genes differentially regulated by CRTC1 in colonic epithelial tumor. Subconfluent Caco-2 cells were transfected with 200ng of CRTC1 expression plasmid or corresponding empty vector (pBS) overnight. N = 4 per group.
2015-01-01 | E-GEOD-59730 | biostudies-arrayexpress