RESEARCH HIGHLIGHTS Nature Reviews Molecular Cell Biology | AOP, published online 27 November 2013; doi:10.1038/nrm3715
M E TA B O L I S M
Young again with Lin28 re-expression of the RNAbinding protein LIN28A … enhances tissue repair by increasing oxidative metabolism
The ability of tissues to repair themselves decreases with age across a range of organisms, but the underlying molecular biology is unclear. Daley and colleagues reveal that, in mice, re-expression of the RNA-binding protein LIN28A, which is highly expressed during embryogenesis and in embryonic stem cells, enhances tissue repair by increasing oxidative metabolism. Lin28a mRNA is expressed in embryonic epidermis and limb buds, but its expression declines in these tissues after birth. The authors observed that epidermal hair regrowth (after shaving) and digit repair (following amputation
2 days after birth) were increased in an inducible Lin28a-transgenic mouse (iLin28a Tg), which expresses low levels of Lin28a in the absence of induction. Inducing Lin28a in adult mice enabled them to undergo hair regrowth even during the resting phase of the hair follicle cycle. Moreover, wounds in the pinnal tissues of the adult outer ear showed enhanced repair in the iLin28a Tg mouse, and repair was further increased when Lin28a expression was actually induced. Thus, the re-expression of Lin28a in mice enhances tissue repair. LIN28A represses the bio genesis of let-7 microRNAs, so Shyh‑Chang et al. asked whether LIN28A enhanced tissue repair through this mechanism. They observed a decrease in let-7 expression after injury to mouse digits and pinnal tissues. In addition, the induced expression of let-7 in a transgenic mouse decreased the level of pinnal tissue repair, suggesting that let-7 must be repressed for this to occur. However, as repressing let-7 alone did not increase pinnal tissue repair or hair regrowth, LIN28A must influence additional factors to promote these biological processes. As LIN28A and let-7 have been shown to regulate glucose metabolism, the authors assessed the metabolic profile of whole embryos deficient in LIN28A. Loss of Lin28a correlated with a decrease in glycolysis. Interestingly, the induction of Lin28a increased glycolysis in pinnal tissues after injury and during tissue repair in vivo; and Lin28a expression
in mouse embryonic fibroblasts (MEFs) increased the flux of glucose into glycolysis and the Krebs cycle. Hence, expression of Lin28a enhances mitochondrial oxidative phosphorylation. The repression of let-7 only partially phenocopied the metabolic state of Lin28a overexpression; so, how does LIN28A increase oxidative phosphorylation? The authors showed that LIN28A bound to mRNAs encoding metabolic enzymes with roles in glycolysis and oxidative phosphorylation, including phosphofructokinase and pyruvate dehydrogenase mRNA, and increased their translation. Interestingly, the enhanced metabolic activity of MEFs from iLin28a Tg mice increased their ability to migrate and proliferate — processes that are important for wound repair — in vitro. The importance of LIN28A-promoted oxidative metabolism for tissue repair was confirmed in vivo, as the topical addition of oxidative phosphorylation inhibitors suppressed the enhanced hair regrowth and pinnal tissue repair in iLin28a Tg mice. Thus, the re-expression of Lin28a in mice enhances tissue repair through a mechanism that requires the repression of let-7 and the ability of LIN28A to regulate oxidative metabolism, a bioenergetic state that is prominent during embryogenesis. Katharine H. Wrighton ORIGINAL RESEARCH PAPER Shyh-Chang, N. et al. Lin28 enhances tissue repair by reprogramming cellular metabolism. Cell 155, 778–792 (2013)
Corbis
NATURE REVIEWS | MOLECULAR CELL BIOLOGY
VOLUME 15 | JANUARY 2014 © 2013 Macmillan Publishers Limited. All rights reserved
M E TA B O L I S M
Young again with Lin28 re-expression of the RNAbinding protein LIN28A … enhances tissue repair by increasing oxidative metabolism
The ability of tissues to repair themselves decreases with age across a range of organisms, but the underlying molecular biology is unclear. Daley and colleagues reveal that, in mice, re-expression of the RNA-binding protein LIN28A, which is highly expressed during embryogenesis and in embryonic stem cells, enhances tissue repair by increasing oxidative metabolism. Lin28a mRNA is expressed in embryonic epidermis and limb buds, but its expression declines in these tissues after birth. The authors observed that epidermal hair regrowth (after shaving) and digit repair (following amputation
2 days after birth) were increased in an inducible Lin28a-transgenic mouse (iLin28a Tg), which expresses low levels of Lin28a in the absence of induction. Inducing Lin28a in adult mice enabled them to undergo hair regrowth even during the resting phase of the hair follicle cycle. Moreover, wounds in the pinnal tissues of the adult outer ear showed enhanced repair in the iLin28a Tg mouse, and repair was further increased when Lin28a expression was actually induced. Thus, the re-expression of Lin28a in mice enhances tissue repair. LIN28A represses the bio genesis of let-7 microRNAs, so Shyh‑Chang et al. asked whether LIN28A enhanced tissue repair through this mechanism. They observed a decrease in let-7 expression after injury to mouse digits and pinnal tissues. In addition, the induced expression of let-7 in a transgenic mouse decreased the level of pinnal tissue repair, suggesting that let-7 must be repressed for this to occur. However, as repressing let-7 alone did not increase pinnal tissue repair or hair regrowth, LIN28A must influence additional factors to promote these biological processes. As LIN28A and let-7 have been shown to regulate glucose metabolism, the authors assessed the metabolic profile of whole embryos deficient in LIN28A. Loss of Lin28a correlated with a decrease in glycolysis. Interestingly, the induction of Lin28a increased glycolysis in pinnal tissues after injury and during tissue repair in vivo; and Lin28a expression
in mouse embryonic fibroblasts (MEFs) increased the flux of glucose into glycolysis and the Krebs cycle. Hence, expression of Lin28a enhances mitochondrial oxidative phosphorylation. The repression of let-7 only partially phenocopied the metabolic state of Lin28a overexpression; so, how does LIN28A increase oxidative phosphorylation? The authors showed that LIN28A bound to mRNAs encoding metabolic enzymes with roles in glycolysis and oxidative phosphorylation, including phosphofructokinase and pyruvate dehydrogenase mRNA, and increased their translation. Interestingly, the enhanced metabolic activity of MEFs from iLin28a Tg mice increased their ability to migrate and proliferate — processes that are important for wound repair — in vitro. The importance of LIN28A-promoted oxidative metabolism for tissue repair was confirmed in vivo, as the topical addition of oxidative phosphorylation inhibitors suppressed the enhanced hair regrowth and pinnal tissue repair in iLin28a Tg mice. Thus, the re-expression of Lin28a in mice enhances tissue repair through a mechanism that requires the repression of let-7 and the ability of LIN28A to regulate oxidative metabolism, a bioenergetic state that is prominent during embryogenesis. Katharine H. Wrighton ORIGINAL RESEARCH PAPER Shyh-Chang, N. et al. Lin28 enhances tissue repair by reprogramming cellular metabolism. Cell 155, 778–792 (2013)
Corbis
NATURE REVIEWS | MOLECULAR CELL BIOLOGY
VOLUME 15 | JANUARY 2014 © 2013 Macmillan Publishers Limited. All rights reserved
