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The let-7/LIN-41 Pathway Regulates Reprogramming to Human Induced Pluripotent Stem Cells by Controlling Expression of Prodifferentiation Genes

2013; Elsevier BV; Volume: 14; Issue: 1 Linguagem: Inglês

10.1016/j.stem.2013.11.001

1934-5909

Kathleen A. Worringer, Tim Rand, Yohei Hayashi, Salma Sami, Kazutoshi Takahashi, Koji Tanabe, Megumi Narita, Deepak Srivastava, Shinya Yamanaka,

CRISPR and Genetic Engineering

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.