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Transcriptional analysis of pluripotency reveals the Hippo pathway as a barrier to reprogramming.

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, and Diabetes Center, South San Francisco, CA, USA.
Human Molecular Genetics (Impact Factor: 6.68). 02/2012; 21(9):2054-67. DOI: 10.1093/hmg/dds023
Source: PubMed

ABSTRACT Pluripotent stem cells are derived from culture of early embryos or the germline and can be induced by reprogramming of somatic cells. Barriers to reprogramming that stabilize the differentiated state and have tumor suppression functions are expected to exist. However, we have a limited understanding of what such barriers might be. To find novel barriers to reprogramming to pluripotency, we compared the transcriptional profiles of the mouse germline with pluripotent and somatic cells, in vivo and in vitro. There is a remarkable global expression of the transcriptional program for pluripotency in primordial germ cells (PGCs). We identify parallels between PGC reprogramming to pluripotency and human germ cell tumorigenesis, including the loss of LATS2, a tumor suppressor kinase of the Hippo pathway. We show that knockdown of LATS2 increases the efficiency of induction of pluripotency in human cells. LATS2 RNAi, unlike p53 RNAi, specifically enhances the generation of fully reprogrammed iPS cells without accelerating cell proliferation. We further show that LATS2 represses reprogramming in human cells by post-transcriptionally antagonizing TAZ but not YAP, two downstream effectors of the Hippo pathway. These results reveal transcriptional parallels between germ cell transformation and the generation of iPS cells and indicate that the Hippo pathway constitutes a barrier to cellular reprogramming.

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Available from: Laure Blouin, Sep 26, 2014
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    • "Importantly, the somatic cell is not a tabula rasa and expresses genes that antagonize reprogramming, as has been shown for tumor suppressors (p53, INK4a/ARF, LATS2) (Kawamura et al., 2009; Qin et al., 2012; Zhao et al., 2008) and H3K9 methyltransferases (SETDB1, SUV39H, EHMT2) (Chen et al., 2013). In addition, focused RNAi screens have revealed other pathways that act as barriers to reprogramming, such as TGF-b signaling (Samavarchi-Tehrani et al., 2010), H3K79 methylation by DOT1L (Onder et al., 2012), or protein ubiquitination (Buckley et al., 2012). "
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    • "By comparing somatic cells with iPSCs, the Hippo pathway gene Lats2 was found to be significantly repressed during reprogramming , and may therefore represent such a barrier (Qin et al., 2012). Indeed, knockdown of Lats2 increased efficiency of human iPSC generation about three fold without accelerating cell proliferation (Qin et al., 2012). The elevated reprogramming efficiency depends on TAZ because concomitant knockdown of TAZ blocked the effect of Lats2 knockdown. "
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