LIN28 Regulates Stem Cell Metabolism and Conversion to Primed Pluripotency

Jin Zhang, Sutheera Ratanasirintrawoot, Sriram Chandrasekaran, Zhaoting Wu, Scott B. Ficarro, Chunxiao Yu, Christian A. Ross, Davide Cacchiarelli, Qing Xia, Marc Seligson, Gen Shinoda, Wen Xie, Patrick Cahan, Longfei Wang, Shyh Chang Ng, Supisara Tintara, Cole Trapnell, Tamer Onder, Yuin Han Loh, Tarjei MikkelsenPiotr Sliz, Michael A. Teitell, John M. Asara, Jarrod A. Marto, Hu Li, James J. Collins, George Q. Daley

Research output: Contribution to journalArticle

118 Scopus citations

Abstract

The RNA-binding proteins LIN28A and LIN28B play critical roles in embryonic development, tumorigenesis, and pluripotency, but their exact functions are poorly understood. Here, we show that, like LIN28A, LIN28B can function effectively with NANOG, OCT4, and SOX2 in reprogramming to pluripotency and that reactivation of both endogenous LIN28A and LIN28B loci are required for maximal reprogramming efficiency. In human fibroblasts, LIN28B is activated early during reprogramming, while LIN28A is activated later during the transition to bona fide induced pluripotent stem cells (iPSCs). In murine cells, LIN28A and LIN28B facilitate conversion from naive to primed pluripotency. Proteomic and metabolomic analysis highlighted roles for LIN28 in maintaining the low mitochondrial function associated with primed pluripotency and in regulating one-carbon metabolism, nucleotide metabolism, and histone methylation. LIN28 binds to mRNAs of proteins important for oxidative phosphorylation and modulates protein abundance. Thus, LIN28A and LIN28B play cooperative roles in regulating reprogramming, naive/primed pluripotency, and stem cell metabolism.

Original languageEnglish (US)
Pages (from-to)66-80
Number of pages15
JournalCell Stem Cell
Volume19
Issue number1
DOIs
StatePublished - Jul 1 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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    Zhang, J., Ratanasirintrawoot, S., Chandrasekaran, S., Wu, Z., Ficarro, S. B., Yu, C., Ross, C. A., Cacchiarelli, D., Xia, Q., Seligson, M., Shinoda, G., Xie, W., Cahan, P., Wang, L., Ng, S. C., Tintara, S., Trapnell, C., Onder, T., Loh, Y. H., ... Daley, G. Q. (2016). LIN28 Regulates Stem Cell Metabolism and Conversion to Primed Pluripotency. Cell Stem Cell, 19(1), 66-80. https://doi.org/10.1016/j.stem.2016.05.009