MYC Releases Early Reprogrammed Human Cells from Proliferation Pause via Retinoblastoma Protein Inhibition
Summary: Here, we report that MYC rescues early human cells undergoing reprogramming from a proliferation pause induced by OCT3/4, SOX2, and KLF4 (OSK). We identified ESRG as a marker of early reprogramming cells that is expressed as early as day 3 after OSK induction. On day 4, ESRG positive (+) ce...
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doaj-6d37ebb8ecc14fb29cca6dcdd36186212020-11-25T01:56:58ZengElsevierCell Reports2211-12472018-04-01232361375MYC Releases Early Reprogrammed Human Cells from Proliferation Pause via Retinoblastoma Protein InhibitionTim A. Rand0Kenta Sutou1Koji Tanabe2Daeun Jeong3Masaki Nomura4Fumiyo Kitaoka5Emi Tomoda6Megumi Narita7Michiko Nakamura8Masahiro Nakamura9Akira Watanabe10Eric Rulifson11Shinya Yamanaka12Kazutoshi Takahashi13Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USADepartment of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, JapanInstitute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USAGladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USADepartment of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, JapanDepartment of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, JapanGladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USADepartment of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, JapanDepartment of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, JapanDepartment of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, JapanDepartment of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, JapanDepartment of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USAGladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan; Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Corresponding authorGladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan; Corresponding authorSummary: Here, we report that MYC rescues early human cells undergoing reprogramming from a proliferation pause induced by OCT3/4, SOX2, and KLF4 (OSK). We identified ESRG as a marker of early reprogramming cells that is expressed as early as day 3 after OSK induction. On day 4, ESRG positive (+) cells converted to a TRA-1-60 (+) intermediate state. These early ESRG (+) or TRA-1-60 (+) cells showed a proliferation pause due to increased p16INK4A and p21 and decreased endogenous MYC caused by OSK. Exogenous MYC did not enhance the appearance of initial reprogramming cells but instead reactivated their proliferation and improved reprogramming efficiency. MYC increased expression of LIN41, which potently suppressed p21 post-transcriptionally. MYC suppressed p16 INK4A. These changes inactivated retinoblastoma protein (RB) and reactivated proliferation. The RB-regulated proliferation pause does not occur in immortalized fibroblasts, leading to high reprogramming efficiency even without exogenous MYC. : Rand et al. find that MYC promotes proliferation of human intermediate reprogrammed cells rather than initiation of reprogramming. MYC post-transcriptionally activates LIN41, resulting in post-transcriptional suppression of p21. Suppression of p21 results in reduction of RB activity, which is a negative regulator of reprogramming progression. Keywords: reprogramming, pluripotency, induced pluripotent stem cell, proliferation, senescence, immortalization, MYC, LIN41, post-transcriptional regulationhttp://www.sciencedirect.com/science/article/pii/S2211124718304029 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Tim A. Rand Kenta Sutou Koji Tanabe Daeun Jeong Masaki Nomura Fumiyo Kitaoka Emi Tomoda Megumi Narita Michiko Nakamura Masahiro Nakamura Akira Watanabe Eric Rulifson Shinya Yamanaka Kazutoshi Takahashi |
spellingShingle |
Tim A. Rand Kenta Sutou Koji Tanabe Daeun Jeong Masaki Nomura Fumiyo Kitaoka Emi Tomoda Megumi Narita Michiko Nakamura Masahiro Nakamura Akira Watanabe Eric Rulifson Shinya Yamanaka Kazutoshi Takahashi MYC Releases Early Reprogrammed Human Cells from Proliferation Pause via Retinoblastoma Protein Inhibition Cell Reports |
author_facet |
Tim A. Rand Kenta Sutou Koji Tanabe Daeun Jeong Masaki Nomura Fumiyo Kitaoka Emi Tomoda Megumi Narita Michiko Nakamura Masahiro Nakamura Akira Watanabe Eric Rulifson Shinya Yamanaka Kazutoshi Takahashi |
author_sort |
Tim A. Rand |
title |
MYC Releases Early Reprogrammed Human Cells from Proliferation Pause via Retinoblastoma Protein Inhibition |
title_short |
MYC Releases Early Reprogrammed Human Cells from Proliferation Pause via Retinoblastoma Protein Inhibition |
title_full |
MYC Releases Early Reprogrammed Human Cells from Proliferation Pause via Retinoblastoma Protein Inhibition |
title_fullStr |
MYC Releases Early Reprogrammed Human Cells from Proliferation Pause via Retinoblastoma Protein Inhibition |
title_full_unstemmed |
MYC Releases Early Reprogrammed Human Cells from Proliferation Pause via Retinoblastoma Protein Inhibition |
title_sort |
myc releases early reprogrammed human cells from proliferation pause via retinoblastoma protein inhibition |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2018-04-01 |
description |
Summary: Here, we report that MYC rescues early human cells undergoing reprogramming from a proliferation pause induced by OCT3/4, SOX2, and KLF4 (OSK). We identified ESRG as a marker of early reprogramming cells that is expressed as early as day 3 after OSK induction. On day 4, ESRG positive (+) cells converted to a TRA-1-60 (+) intermediate state. These early ESRG (+) or TRA-1-60 (+) cells showed a proliferation pause due to increased p16INK4A and p21 and decreased endogenous MYC caused by OSK. Exogenous MYC did not enhance the appearance of initial reprogramming cells but instead reactivated their proliferation and improved reprogramming efficiency. MYC increased expression of LIN41, which potently suppressed p21 post-transcriptionally. MYC suppressed p16 INK4A. These changes inactivated retinoblastoma protein (RB) and reactivated proliferation. The RB-regulated proliferation pause does not occur in immortalized fibroblasts, leading to high reprogramming efficiency even without exogenous MYC. : Rand et al. find that MYC promotes proliferation of human intermediate reprogrammed cells rather than initiation of reprogramming. MYC post-transcriptionally activates LIN41, resulting in post-transcriptional suppression of p21. Suppression of p21 results in reduction of RB activity, which is a negative regulator of reprogramming progression. Keywords: reprogramming, pluripotency, induced pluripotent stem cell, proliferation, senescence, immortalization, MYC, LIN41, post-transcriptional regulation |
url |
http://www.sciencedirect.com/science/article/pii/S2211124718304029 |
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