The let-7/LIN-41 pathway regulates reprogramming to human induced pluripotent stem cells by controlling expression of prodifferentiation genes

  • Cell Stem Cell. 2014 Jan 2;14(1):40-52. doi: 10.1016/j.stem.2013.11.001.
Kathleen A Worringer  1 ,  Tim A Rand  1 ,  Yohei Hayashi  1 ,  Salma Sami  1 ,  Kazutoshi Takahashi  2 ,  Koji Tanabe  2 ,  Megumi Narita  2 ,  Deepak Srivastava  3 ,  Shinya Yamanaka  4
Affiliations
  • 1. Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA.
  • 2. Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
  • 3. Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA; Departments of Pediatrics and Biochemistry & Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: [email protected].
  • 4. Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA; 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. Electronic address: [email protected].
PMID: 24239284 DOI: 10.1016/j.stem.2013.11.001
Abstract

Reprogramming differentiated cells into induced pluripotent stem cells (iPSCs) promotes a broad array of cellular changes. Here we show that the let-7 family of MicroRNAs acts as an inhibitory influence on the reprogramming process through a regulatory pathway involving prodifferentiation factors, including EGR1. Inhibiting let-7 in human cells promotes reprogramming to a comparable extent to c-Myc when combined with OCT4, SOX2, and KLF4, and persistence of let-7 inhibits reprogramming. Inhibiting let-7 during reprogramming leads to an increase in the level of the let-7 target LIN-41/TRIM71, which in turn promotes reprogramming and is important for overcoming the let-7 barrier to reprogramming. Mechanistic studies revealed that LIN-41 regulates a broad array of differentiation genes, and more specifically, inhibits translation of EGR1 through binding its cognate mRNA. Together our findings outline a let-7-based pathway that counteracts the activity of reprogramming factors through promoting the expression of prodifferentiation genes.