Overlapping and distinct roles of LIN28 paralogs in reprogramming and stem cell metabolism

The RNA binding protein paralogs LIN28A and LIN28B play critical roles in embryonic development, tumorigenesis, and pluripotency. Somatic cells can be reprogrammed to induced pluripotent stem (iPS) cells by overexpression of OCT4 and SOX2 together with NANOG and LIN28A (OSNA), but the exact roles LIN28A/B play are still poorly understood. Here we show that LIN28B likewise promotes reprogramming, and that reactivation of both endogenous LIN28A and B loci are required for maximal reprogramming efficiency. The LIN28B locus has open chromatin and is activated early during reprogramming, whereas LIN28A is activated at later stages by OCT4, marking the transition to bona fide iPS cells. By proteomic and metabolomic analysis, we demonstrate that LIN28A chiefly regulates let-7 and protein translation, whereas LIN28B promotes embryonic metabolism by repressing oxidative phosphorylation and enhancing glycolysis. Thus, LIN28A and LIN28B play independent and cooperative roles in reprogramming and pluripotent stem cell metabolism. 8 samples in total were analyzed. 2 replicates for each phenotypes. Controls are the wild type (flox) without lin28a/b loss of function.