LIN28 Regulates Stem Cell Metabolism and Conversion to Primed Pluripotency

• Published in: Cell stem cell 2016-07, Vol.19 (1), p.66-80
• Main Authors: Zhang, Jin, Ratanasirintrawoot, Sutheera, Chandrasekaran, Sriram, Wu, Zhaoting, Ficarro, Scott B., Yu, Chunxiao, Ross, Christian A., Cacchiarelli, Davide, Xia, Qing, Seligson, Marc, Shinoda, Gen, Xie, Wen, Cahan, Patrick, Wang, Longfei, Ng, Shyh-Chang, Tintara, Supisara, Trapnell, Cole, Onder, Tamer, Loh, Yuin-Han, Mikkelsen, Tarjei, Sliz, Piotr, Teitell, Michael A., Asara, John M., Marto, Jarrod A., Li, Hu, Collins, James J., Daley, George Q.
• Format: Article
• Language: English
• Subjects: Animals; Carbon - metabolism; Cellular Reprogramming; DNA-Binding Proteins - metabolism; Fibroblasts - metabolism; Histones - metabolism; Humans; Methylation; Mice; Nucleotides - metabolism; Oxidation-Reduction; Oxidative Phosphorylation; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - metabolism; Proteome - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-Binding Proteins - metabolism
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2016.05.009

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. [Display omitted] •LIN28B functions equivalently to LIN28A in reprogramming to pluripotency•In mouse, LIN28A and LIN28B facilitate transition from naive to primed pluripotency•LIN28 regulates mouse iPSC metabolism by let-7-dependent and -independent mechanisms•LIN28 binding to mRNAs regulates the metabolic proteome Zhang et al. show that the RNA binding protein LIN28A and its closely related paralog, LIN28B, play a key role in regulating pluripotent stem cell metabolism, including during reprogramming and pluripotency state transitions.