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Chitilian J.M.,Lawson Health Research Institute | Chitilian J.M.,University of Western Ontario | Thillainadesan G.,Lawson Health Research Institute | Thillainadesan G.,University of Western Ontario | And 9 more authors.
Stem Cells | Year: 2014

p/CIP, also known as steroid receptor coactivator 3 (SRC-3)/Nuclear Receptor Coactivator 3 (NCoA3), is a transcriptional coactivator that binds liganded nuclear hormone receptors, as well as other transcription factors, and facilitates transcription through direct recruitment of accessory factors. We have found that p/CIP is highly expressed in undifferentiated mouse embryonic stem cells (mESCs) and is downregulated during differentiation. siRNA-mediated knockdown of p/CIP decreased transcript levels of Nanog, but not Oct4 or Sox2. Microarray expression analysis showed that Klf4, Tbx3, and Dax-1 are significantly downregulated in mESCs when p/CIP is knocked down. Subsequent chromatin immunoprecipitation (ChIP) analysis demonstrated that Tbx3, Klf4, and Dax-1 are direct transcriptional targets of p/CIP. Using the piggyBac transposition system, a mouse ESC line that expresses Flag-p/CIP in a doxycycline-dependent manner was generated. p/CIP overexpression increased the level of target genes and promoted the formation of undifferentiated colonies. Collectively, these results indicate that p/CIP contributes to the maintenance of ESC pluripotency through direct regulation of essential pluripotency genes. To better understand the mechanism by which p/ CIP functions in ESC pluripotency, we integrated our ChIP and transcriptome data with published protein-protein interaction and promoter occupancy data to draft a p/CIP gene regulatory network. The p/CIP gene regulatory network identifies various feed-forward modules including one in which p/CIP activates members of the extended pluripotency network, demonstrating that p/CIP is a component of this extended network.© AlphaMed Press 2013. Source

Chang W.Y.,Ottawa Hospital Research Institute | Garcha K.,Center for the Commercialization of Regenerative Medicine | Manias J.L.,Ottawa Hospital Research Institute | Manias J.L.,University of Ottawa | And 4 more authors.
Wiley Interdisciplinary Reviews: Systems Biology and Medicine | Year: 2012

The recent discovery that adult mouse and human somatic cells can be 'reprogrammed' to a state of pluripotency by ectopic expression of only a few transcription factors has already made a major impact on the biomedical community. For the first time, it is possible to study diseases on an individual patient basis, which may eventually lead to the realization of personalized medicine. The utility of induced-pluripotent stem cells (iPSCs) for modeling human diseases has greatly benefitted from established human embryonic stem cell (ESC) differentiation and tissue engineering protocols developed to generate many different cell and tissue types. The limited access to preimplantation genetic tested embryos and the difficulty in gene targeting human ESCs have restricted the use of human ESCs in modeling human disease. Afforded by iPSC technology is the ability to study disease pathogenesis as it unfolds during tissue morphogenesis. The complexities of molecular signaling and interplay with protein transduction during disease progression necessitate a systems approach to studying human diseases, whereby data can be statistically integrated by sorting out the signal to noise issues that arise from global biological changes associated with disease versus experimental noise. Using a systems approach, biomarkers can be identified that define the initiation or progression of disease and likewise can serve as putative therapeutic targets. © 2012 Wiley Periodicals, Inc. Source

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