Inhibition of pluripotency networks by the Rb tumor suppressor restricts reprogramming and tumorigenesis

Authors

Michael S. Kareta, Stanford University
Laura L. Gorges, Stanford University
Sana Hafeez, Stanford University School of Medicine
Bérénice A. Benayoun, Stanford University
Samuele Marro, Stanford University School of Medicine
Anne Flore Zmoos, Stanford University
Matthew J. Cecchini, Western University
Damek Spacek, Stanford University
Luis F.Z. Batista, Stanford University
Megan O'Brien, Stanford University
Yi Han Ng, Stanford University School of Medicine
Cheen Euong Ang, Stanford University School of Medicine
Dedeepya Vaka, Stanford University
Steven E. Artandi, Stanford University
Frederick A. Dick, Western UniversityFollow
Anne Brunet, Stanford University
Julien Sage, Stanford University
Marius Wernig, Stanford University School of Medicine

Document Type

Article

Publication Date

1-1-2015

Journal

Cell Stem Cell

Volume

16

Issue

1

First Page

39

Last Page

50

URL with Digital Object Identifier

10.1016/j.stem.2014.10.019

Abstract

Mutations in the retinoblastoma tumor suppressor gene Rb are involved in many forms of human cancer. In this study, we investigated the early consequences of inactivating Rb in the context of cellular reprogramming. We found that Rb inactivation promotes the reprogramming of differentiated cells to a pluripotent state. Unexpectedly, this effect is cell cycle independent, and instead reflects direct binding of Rb to pluripotency genes, including Sox2 and Oct4, which leads to a repressed chromatin state. More broadly, this regulation of pluripotency networks and Sox2 in particular is critical for the initiation of tumors upon loss of Rb in mice. These studies therefore identify Rb as a global transcriptional repressor of pluripotency networks, providing a molecular basis for previous reports about its involvement in cell fate pliability, and implicate misregulation of pluripotency factors such as Sox2 in tumorigenesis related to loss of Rb function.