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E-GEOD-57718 - Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival [microarray]

Status
Released on 20 February 2015, last updated on 1 March 2015
Organism
Mus musculus
Samples (6)
Array (1)
Protocols (7)
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.
Experiment type
transcription profiling by array 
Contacts
Alexander von Gise, Fei Gu, Haidong Guo, Pim R van Gorp, Pingzhu Zhou, Qing Ma, William T Pu
Citation
Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival. Lin Z, Zhou P, von Gise A, Gu F, Ma Q, Chen J, Guo H, van Gorp PR, Wang DZ, Pu WT. , PMID:25249570
MIAME
PlatformsProtocolsVariablesProcessedRaw
Files
Investigation descriptionE-GEOD-57718.idf.txt
Sample and data relationshipE-GEOD-57718.sdrf.txt
Raw data (1)E-GEOD-57718.raw.1.zip
Processed data (1)E-GEOD-57718.processed.1.zip
Array designA-AFFY-130.adf.txt
Links