LIN28 Regulates Stem Cell Metabolism and Conversion to Primed Pluripotency

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.

Rewiring of embryonic glucose metabolism via suppression of PFK-1 and aldolase during mouse chorioallantoic branching

“…glucose metabolism Zhang et al, 2016). Lin28a mRNA is reported to be expressed throughout the embryo at E8.5, but gradually becomes restricted to the posterior part of embryos as development proceeds (Balzer et al, 2010), resembling the dynamic expression pattern of Aldoa during CB (Fig.…”

Control of embryonic stem cell self-renewal and differentiation via coordinated alternative splicing and translation of YY2

“…Although the transcriptional regulatory network safeguarding the naive/primed state of pluripotency has been studied extensively, the role of posttranscriptional control mechanisms, particularly translational control, remained largely unexplored. The importance of posttranscriptional regulatory processes has been highlighted recently by the identification of the RNA-binding proteins Pum1 and Lin28 as regulators of naive/primed pluripotency (60,61). Detailed analysis of mRNA translation therefore should provide valuable information about the role of translational control in these pluripotent states.…”

Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination

“…An increasing number of studies have demonstrated that cellular metabolism also plays an essential role in regulation of pluripotency, specifically through modulation of the epigenetic landscape (Zhou et al, 2012;Sperber et al, 2015;Zhang et al, 2016). In primed human PSCs, metabolism typically proceeds via the glycolytic pathway, which rapidly switches to oxidative phosphorylation upon differentiation (Zhou et al, 2012;Moussaieff et al, 2015).…”