Journal Article

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

Han Qin, Kathryn Blaschke, Grace Wei, Yuki Ohi, Laure Blouin, Zhongxia Qi, Jingwei Yu, Ru-Fang Yeh, Matthias Hebrok and Miguel Ramalho-Santos

in Human Molecular Genetics

Volume 21, issue 9, pages 2054-2067
Published in print May 2012 | ISSN: 0964-6906
Published online January 2012 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/dds023
Transcriptional analysis of pluripotency reveals the Hippo pathway as a barrier to reprogramming

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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.

Journal Article.  8869 words.  Illustrated.

Subjects: Genetics and Genomics

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