Progesterone, via yes-associated protein (YAP), promotes cardiomyocyte proliferation and cardiac repair
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ABSTRACT:
PROVIDER: PRJNA608653 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11177838_1.fastq.gz | Fastqsanger.gz | |||
| SRR11177838_2.fastq.gz | Fastqsanger.gz | |||
| SRR11177839_1.fastq.gz | Fastqsanger.gz | |||
| SRR11177839_2.fastq.gz | Fastqsanger.gz | |||
| SRR11177840_1.fastq.gz | Fastqsanger.gz |
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Project description:To explore effect of progesterone on gene expression of primary cultured cardiomyocytes isolated from 7-day-old SD rats
2020-02-26 | GSE145882 | GEO
Project description:Background—YAP, the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEAD sequence specific DNA-binding proteins. Recent studies showed that YAP stimulates cardiomyocyte proliferation and survival. However, the direct transcriptional targets through which YAP exerts its effects are poorly defined. Methods and Results—To identify genes directly regulated by YAP in cardiomyocytes, we combined differential gene expression analysis in YAP gain- and loss-of-function with genome-wide identification of YAP bound loci using chromatin immunoprecipitation and high throughput sequencing. This screen identified Pik3cb, encoding p110β, a catalytic subunit of phosphoinositol-3-kinase (PI3K), as a candidate YAP effector that promotes cardiomyocyte proliferation and survival. We validated YAP and TEAD occupancy of a conserved enhancer within the first intron of Pik3cb, and show that this enhancer drives YAP-dependent reporter gene expression. Yap gain- and loss-of-function studies indicated that YAP is necessary and sufficient to activate the PI3K-Akt pathway. Like Yap, Pik3cb gain-of-function stimulated cardiomyocyte proliferation, and Pik3cb knockdown dampened the YAP mitogenic activity. Reciprocally, Yap loss-of-function impaired heart function and reduced cardiomyocyte proliferation and survival, all of which were significantly rescued by AAV-mediated Pik3cb expression. Conclusion—Pik3cb is a crucial direct target of YAP, through which the YAP activates PI3K-AKT pathway and regulates cardiomyocyte proliferation and survival. Yap wild type ChIPseq and input
2015-02-20 | E-GEOD-57717 | biostudies-arrayexpress
Project description:Background—YAP, the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEAD sequence specific DNA-binding proteins. Recent studies showed that YAP stimulates cardiomyocyte proliferation and survival. However, the direct transcriptional targets through which YAP exerts its effects are poorly defined. Methods and Results—To identify genes directly regulated by YAP in cardiomyocytes, we combined differential gene expression analysis in YAP gain- and loss-of-function with genome-wide identification of YAP bound loci using chromatin immunoprecipitation and high throughput sequencing. This screen identified Pik3cb, encoding p110β, a catalytic subunit of phosphoinositol-3-kinase (PI3K), as a candidate YAP effector that promotes cardiomyocyte proliferation and survival. We validated YAP and TEAD occupancy of a conserved enhancer within the first intron of Pik3cb, and show that this enhancer drives YAP-dependent reporter gene expression. Yap gain- and loss-of-function studies indicated that YAP is necessary and sufficient to activate the PI3K-Akt pathway. Like Yap, Pik3cb gain-of-function stimulated cardiomyocyte proliferation, and Pik3cb knockdown dampened the YAP mitogenic activity. Reciprocally, Yap loss-of-function impaired heart function and reduced cardiomyocyte proliferation and survival, all of which were significantly rescued by AAV-mediated Pik3cb expression. Conclusion—Pik3cb is a crucial direct target of YAP, through which the YAP activates PI3K-AKT pathway and regulates cardiomyocyte proliferation and survival. Two groups were involved in this study:TNTcreYapfl_het group and TNTcreYapfl_KO group. Each group contained three biological replicates. Embryo hearts were collected at E12.5 and dissociated. Cardiomyocytes were collected by FACS. The total RNA of cardiomyocytes were isolated for microarray analysis.
2015-02-20 | E-GEOD-57718 | biostudies-arrayexpress
Project description:ObjectivesThe mechanisms responsible for the postnatal loss of mammalian cardiac regenerative capacity are not fully elucidated. The aim of the present study is to investigate the role of progesterone in cardiac regeneration and explore underlying mechanism.Materials and methodsEffect of progesterone on cardiomyocyte proliferation was analysed by immunofluorescent staining. RNA sequencing was performed to screen key target genes of progesterone, and yes-associated protein (YAP) was knocked down to demonstrate its role in pro-proliferative effect of progesterone. Effect of progesterone on activity of YAP promoter was measured by luciferase assay and interaction between progesterone receptor and YAP promoter by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP). Adult mice were subjected to myocardial infarction, and then, effects of progesterone on adult cardiac regeneration were analysed.ResultsProgesterone supplementation enhanced cardiomyocyte proliferation in a progesterone receptor-dependent manner. Progesterone up-regulated YAP expression and knockdown of YAP by small interfering RNA reduced progesterone-mediated cardiomyocyte proliferative effect. Progesterone receptor interacted with the YAP promoter, determined by ChIP and EMSA; progesterone increased luciferase activity of YAP promoter and up-regulated YAP target genes. Progesterone administration also promoted adult cardiomyocyte proliferation and improved cardiac function in myocardial infarction.ConclusionOur data uncover a role of circulating progesterone withdrawal as a novel mechanism for the postnatal loss of mammalian cardiac regenerative potential. Progesterone promotes both neonatal and adult cardiomyocyte proliferation by up-regulating YAP expression.
| S-EPMC7653240 | biostudies-literature
Project description:Background—YAP, the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEAD sequence specific DNA-binding proteins. Recent studies showed that YAP stimulates cardiomyocyte proliferation and survival. However, the direct transcriptional targets through which YAP exerts its effects are poorly defined. Methods and Results—To identify genes directly regulated by YAP in cardiomyocytes, we combined differential gene expression analysis in YAP gain- and loss-of-function with genome-wide identification of YAP bound loci using chromatin immunoprecipitation and high throughput sequencing. This screen identified Pik3cb, encoding p110β, a catalytic subunit of phosphoinositol-3-kinase (PI3K), as a candidate YAP effector that promotes cardiomyocyte proliferation and survival. We validated YAP and TEAD occupancy of a conserved enhancer within the first intron of Pik3cb, and show that this enhancer drives YAP-dependent reporter gene expression. Yap gain- and loss-of-function studies indicated that YAP is necessary and sufficient to activate the PI3K-Akt pathway. Like Yap, Pik3cb gain-of-function stimulated cardiomyocyte proliferation, and Pik3cb knockdown dampened the YAP mitogenic activity. Reciprocally, Yap loss-of-function impaired heart function and reduced cardiomyocyte proliferation and survival, all of which were significantly rescued by AAV-mediated Pik3cb expression. Conclusion—Pik3cb is a crucial direct target of YAP, through which the YAP activates PI3K-AKT pathway and regulates cardiomyocyte proliferation and survival.
2015-02-20 | GSE57718 | GEO
Project description:Background—YAP, the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEAD sequence specific DNA-binding proteins. Recent studies showed that YAP stimulates cardiomyocyte proliferation and survival. However, the direct transcriptional targets through which YAP exerts its effects are poorly defined. Methods and Results—To identify genes directly regulated by YAP in cardiomyocytes, we combined differential gene expression analysis in YAP gain- and loss-of-function with genome-wide identification of YAP bound loci using chromatin immunoprecipitation and high throughput sequencing. This screen identified Pik3cb, encoding p110β, a catalytic subunit of phosphoinositol-3-kinase (PI3K), as a candidate YAP effector that promotes cardiomyocyte proliferation and survival. We validated YAP and TEAD occupancy of a conserved enhancer within the first intron of Pik3cb, and show that this enhancer drives YAP-dependent reporter gene expression. Yap gain- and loss-of-function studies indicated that YAP is necessary and sufficient to activate the PI3K-Akt pathway. Like Yap, Pik3cb gain-of-function stimulated cardiomyocyte proliferation, and Pik3cb knockdown dampened the YAP mitogenic activity. Reciprocally, Yap loss-of-function impaired heart function and reduced cardiomyocyte proliferation and survival, all of which were significantly rescued by AAV-mediated Pik3cb expression. Conclusion—Pik3cb is a crucial direct target of YAP, through which the YAP activates PI3K-AKT pathway and regulates cardiomyocyte proliferation and survival.
2015-02-20 | GSE57717 | GEO
Project description:Hepatocellular carcinoma (HCC) is a disease with high unmet medical need. Most patients are diagnosed at late stage with few therapeutic options and a dismal prognosis. While molecular genomic studies have been helpful in improving the understanding and treatment of many types of cancer, their impact on HCC has been negligible so far. This is largely due to a poor understanding of the underlying mechanisms of this cancer and the lack of dominant oncogene that can be targeted pharmacologically. Here we report the identification of a novel Yes oncogenic signaling pathway in HCC that has escaped large-scale molecular genetic studies. Using a combination of genetic and pharmacological interventions in cellular and mouse models of HCC, we show that Yes activity is necessary for HCC cell proliferation. Transgenic expression of activated Yes in mouse hepatocytes is sufficient to induce liver tumorigenesis. Mechanistically, we found that Yes directly phosphorylates YAP and TAZ, promoting their nuclear accumulation and transcriptional activity in HCC cells and liver tumors, and that YAP/TAZ are effectors of Yes oncogenic transformation. Src-family kinase activation correlates with YAP tyrosine phosphorylation and nuclear localization in human HCC, and is associated with increased tumor burden. Specifically, high Yes activity predicts significantly shorter overall survival in HCC patients. Our findings identify Yes as a potential therapeutic target in HCC.
2022-01-05 | GSE179751 | GEO
Project description:Hepatocellular carcinoma (HCC) is a disease with high unmet medical need. Most patients are diagnosed at late stage with few therapeutic options and a dismal prognosis. While molecular genomic studies have been helpful in improving the understanding and treatment of many types of cancer, their impact on HCC has been negligible so far. This is largely due to a poor understanding of the underlying mechanisms of this cancer and the lack of dominant oncogene that can be targeted pharmacologically. Here we report the identification of a novel Yes oncogenic signaling pathway in HCC that has escaped large-scale molecular genetic studies. Using a combination of genetic and pharmacological interventions in cellular and mouse models of HCC, we show that Yes activity is necessary for HCC cell proliferation. Transgenic expression of activated Yes in mouse hepatocytes is sufficient to induce liver tumorigenesis. Mechanistically, we found that Yes directly phosphorylates YAP and TAZ, promoting their nuclear accumulation and transcriptional activity in HCC cells and liver tumors, and that YAP/TAZ are effectors of Yes oncogenic transformation. Src-family kinase activation correlates with YAP tyrosine phosphorylation and nuclear localization in human HCC, and is associated with increased tumor burden. Specifically, high Yes activity predicts significantly shorter overall survival in HCC patients. Our findings identify Yes as a potential therapeutic target in HCC.
2022-01-05 | GSE179749 | GEO
Project description:Hepatocellular carcinoma (HCC) is a disease with high unmet medical need. Most patients are diagnosed at late stage with few therapeutic options and a dismal prognosis. While molecular genomic studies have been helpful in improving the understanding and treatment of many types of cancer, their impact on HCC has been negligible so far. This is largely due to a poor understanding of the underlying mechanisms of this cancer and the lack of dominant oncogene that can be targeted pharmacologically. Here we report the identification of a novel Yes oncogenic signaling pathway in HCC that has escaped large-scale molecular genetic studies. Using a combination of genetic and pharmacological interventions in cellular and mouse models of HCC, we show that Yes activity is necessary for HCC cell proliferation. Transgenic expression of activated Yes in mouse hepatocytes is sufficient to induce liver tumorigenesis. Mechanistically, we found that Yes directly phosphorylates YAP and TAZ, promoting their nuclear accumulation and transcriptional activity in HCC cells and liver tumors, and that YAP/TAZ are effectors of Yes oncogenic transformation. Src-family kinase activation correlates with YAP tyrosine phosphorylation and nuclear localization in human HCC, and is associated with increased tumor burden. Specifically, high Yes activity predicts significantly shorter overall survival in HCC patients. Our findings identify Yes as a potential therapeutic target in HCC.
2022-01-05 | GSE179750 | GEO
Project description:Hepatocellular carcinoma (HCC) is a disease with high unmet medical need. Most patients are diagnosed at late stage with few therapeutic options and a dismal prognosis. While molecular genomic studies have been helpful in improving the understanding and treatment of many types of cancer, their impact on HCC has been negligible so far. This is largely due to a poor understanding of the underlying mechanisms of this cancer and the lack of dominant oncogene that can be targeted pharmacologically. Here we report the identification of a novel Yes oncogenic signaling pathway in HCC that has escaped large-scale molecular genetic studies. Using a combination of genetic and pharmacological interventions in cellular and mouse models of HCC, we show that Yes activity is necessary for HCC cell proliferation. Transgenic expression of activated Yes in mouse hepatocytes is sufficient to induce liver tumorigenesis. Mechanistically, we found that Yes directly phosphorylates YAP and TAZ, promoting their nuclear accumulation and transcriptional activity in HCC cells and liver tumors, and that YAP/TAZ are effectors of Yes oncogenic transformation. Src-family kinase activation correlates with YAP tyrosine phosphorylation and nuclear localization in human HCC, and is associated with increased tumor burden. Specifically, high Yes activity predicts significantly shorter overall survival in HCC patients. Our findings identify Yes as a potential therapeutic target in HCC.
2022-01-05 | GSE179748 | GEO