MYC Releases Early Reprogrammed Human Cells from Proliferation Pause via Retinoblastoma Protein Inhibition

• Published in: Cell reports (Cambridge) Vol. 23; no. 2; pp. 361 - 375
• Main Authors: Rand, Tim A., Sutou, Kenta, Tanabe, Koji, Jeong, Daeun, Nomura, Masaki, Kitaoka, Fumiyo, Tomoda, Emi, Narita, Megumi, Nakamura, Michiko, Nakamura, Masahiro, Watanabe, Akira, Rulifson, Eric, Yamanaka, Shinya, Takahashi, Kazutoshi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.04.2018; Elsevier
• Subjects: immortalization; induced pluripotent stem cell; LIN41; MYC; pluripotency; post-transcriptional regulation; proliferation; reprogramming; senescence; reprogramming; senescence; induced pluripotent stem cell; proliferation; immortalization; MYC; post-transcriptional regulation; pluripotency; LIN41
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.03.057

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. [Display omitted] •ESRG (+) early reprogramming cells do not proliferate due to RB activation•MYC does not facilitate appearance of ESRG (+) cells but induces their proliferation•MYC inactivates RB by suppressing p16 and p21, with the latter mediated through LIN41•Immortalized cells show efficient reprogramming 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.