Lin28 Enhances Tissue Repair by Reprogramming Cellular Metabolism

SummaryRegeneration capacity declines with age, but why juvenile organisms show enhanced tissue repair remains unexplained. Lin28a, a highly conserved RNA-binding protein expressed during embryogenesis, plays roles in development, pluripotency, and metabolism. To determine whether Lin28a might influence tissue repair in adults, we engineered the reactivation of Lin28a expression in several models of tissue injury. Lin28a reactivation improved hair regrowth by promoting anagen in hair follicles and accelerated regrowth of cartilage, bone, and mesenchyme after ear and digit injuries. Lin28a inhibits let-7 microRNA biogenesis; however, let-7 repression was necessary but insufficient to enhance repair. Lin28a bound to and enhanced the translation of mRNAs for several metabolic enzymes, thereby increasing glycolysis and oxidative phosphorylation (OxPhos). Lin28a-mediated enhancement of tissue repair was negated by OxPhos inhibition, whereas a pharmacologically induced increase in OxPhos enhanced repair. Thus, Lin28a enhances tissue repair in some adult tissues by reprogramming cellular bioenergetics.PaperCli

LIN28 phosphorylation by MAPK/ERK couples signaling to the post-transcriptional control of pluripotency

Signaling and post-transcriptional gene control are both critical for the regulation of pluripotency1,2, yet how they are integrated to influence cell identity remains poorly understood. LIN28 (also known as LIN28A), a highly conserved RNA-binding protein (RBP), has emerged as a central post-transcriptional regulator of cell fate through blockade of let-7 microRNA (miRNA) biogenesis and direct modulation of mRNA translation3. Here we show that LIN28 is phosphorylated by MAPK/ERK in pluripotent stem cells (PSCs), which increases its levels via post-translational stabilization. LIN28 phosphorylation had little impact on let-7 but enhanced LIN28’s effect on its direct mRNA targets, revealing a mechanism that uncouples LIN28’s let-7-dependent and independent activities. We have linked this mechanism to the induction of pluripotency by somatic cell reprogramming and the transition from naïve to primed pluripotency. Collectively, our findings indicate that MAPK/ERK directly impacts LIN28, defining an axis that connects signaling, post-transcriptional gene control, and cell fate regulation

Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma

Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumour suppressor family of microRNAs implicated in numerous cancers. LIN28B, an inhibitor of let-7 biogenesis, is overexpressed in neuroblastoma and has been reported to regulate MYCN. Here we show, however, that LIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. We further demonstrate that MYCN messenger RNA levels in amplified disease are exceptionally high and sufficient to sponge let-7, which reconciles the dispensability of LIN28B. We found that genetic loss of let-7 is common in neuroblastoma, inversely associated with MYCN amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. We propose that let-7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma development with broad implications for cancer pathogenesis.United States. National Institutes of Health (R01GM107536)Alex's Lemonade Stand FoundationHoward Hughes Medical InstituteBoston Children's Hospital. Manton Center for Orphan Disease ResearchNational Institute of General Medical Sciences (U.S.) (T32GM007753

Precise let-7 expression levels balance organ regeneration against tumor suppression

The in vivo roles for even the most intensely studied microRNAs remain poorly defined. Here, analysis of mouse models revealed that let-7, a large and ancient microRNA family, performs tumor suppressive roles at the expense of regeneration. Too little or too much let-7 resulted in compromised protection against cancer or tissue damage, respectively. Modest let-7 overexpression abrogated MYC-driven liver cancer by antagonizing multiple let-7 sensitive oncogenes. However, the same level of overexpression blocked liver regeneration, while let-7 deletion enhanced it, demonstrating that distinct let-7 levels can mediate desirable phenotypes. let-7 dependent regeneration phenotypes resulted from influences on the insulin-PI3K-mTOR pathway. We found that chronic high-dose let-7 overexpression caused liver damage and degeneration, paradoxically leading to tumorigenesis. These dose-dependent roles for let-7 in tissue repair and tumorigenesis rationalize the tight regulation of this microRNA in development, and have important implications for let-7 based therapeutics. DOI: http://dx.doi.org/10.7554/eLife.09431.00

La desigualdad en la tenencia de la tierra: una comparación de los datos de los censos y de los registros de propiedad en el sur de Costa Rica en el siglo XX

Al menos desde el tiempo de Aristóteles, la desigualdad de la tierra ha sido vista como causa de revoluciones y disturbios sociales. La mayoría de las revoluciones del siglo XX han estado vinculadas con la desigualdad agraria. Este articulo no se centra en los asuntos de la desigualdad y la insurgencia per se, sino que examina mas bien una significativa pero pocas veces atendida cuestión epistemológica: la validez de los datos de los censos agrícolas que sustentan la mayor parte de las investigaciones comparativas sobre disturbios sociales rurales. Nuestro análisis emplea un rico conjunto de datos de censos computarizados a la par de los datos de los registros mercantil, de la propiedad y del catastro que nos permiten examinar la misma área física a través de lentes diferentes y en tiempos distintos. Los datos provienen del cantón de Coto Brus, Costa Rica, un área que estaba siendo colonizada durante el periodo para el cual disponemos de datos de los censos agrícolas. Mostramos que el uso aísla do, ya sea de los datos de los censos o de los datos del registro, para la estimación de la concentración de la tierra puede ser muy inexacto. Esto puede explicar por que investigaciones anteriores han conducido con frecuencia a conclusiones equivocadas

Celiac artery occlusion from median arcuate ligament compression complicating a hemorrhagic duodenal ulcer repair

We present a case of a hemorrhagic duodenal ulcer complicated by occlusion of the celiac artery (CA) by acute median arcuate ligament (MAL) compression. Angiography revealed retrograde flow through the gastroduodenal artery (GDA) to the hepatic artery, with occlusion at the CA origin. This unique presentation required coordinated release of the MAL to reestablish antegrade CA flow before pyloroplasty and GDA ligation. The presence of preexisting MAL compression of the CA should be considered during the repair of bleeding duodenal ulcers through embolization or ligation of the GDA, because impaired CA perfusion could result in foregut ischemia

Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma

Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumor suppressor family of microRNAs implicated in numerous cancers. LIN28B, an inhibitor of let-7 biogenesis, is overexpressed in neuroblastoma and has been reported to regulate MYCN. However, here we show that LIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. We further demonstrate that MYCN mRNA levels in amplified disease are exceptionally high and sufficient to sponge let-7, which reconciles the dispensability of LIN28B. We found that genetic loss of let-7 is common in neuroblastoma, inversely associated with MYCN-amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. We propose that let-7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma pathogenesis with broad implications for cancer pathogenesis

LIN28 Regulates Stem Cell Metabolism and Conversion to Primed Pluripotency

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.Howard Hughes Medical Institute; SysCODE (Systems-based Consortium for Organ Design Engineering); NIH [RL1DE019021, CA196631-01A1, 1U54GM114838-01, R01GM107536, P50GM099117, U01 HL100001, P01CA120964, S10RR032861, P30CA006516]; Mayo Clinic Foundation; Mayo Clinic Center for Individualized Medicine; Ellison Medical FoundationSCI(E)[email protected]