Lactate-dependent transcriptional regulation controls mammalian eye morphogenesis.

Mammalian retinal metabolism favors aerobic glycolysis. However, the role of glycolytic metabolism in retinal morphogenesis remains unknown. We report that aerobic glycolysis is necessary for the early stages of retinal development. Taking advantage of an unbiased approach that combines the use of eye organoids and single-cell RNA sequencing, we identify specific glucose transporters and glycolytic genes in retinal progenitors. Next, we determine that the optic vesicle territory of mouse embryos displays elevated levels of glycolytic activity. At the functional level, we show that removal of Glucose transporter 1 and Lactate dehydrogenase A gene activity from developing retinal progenitors arrests eye morphogenesis. Surprisingly, we uncover that lactate-mediated upregulation of key eye-field transcription factors is controlled by the epigenetic modification of histone H3 acetylation through histone deacetylase activity. Our results identify an unexpected bioenergetic independent role of lactate as a signaling molecule necessary for mammalian eye morphogenesis.

Differential DNA methylation and transcriptional signatures characterize impairment of muscle stem cells in pediatric human muscle contractures after brain injury.

Limb contractures are a debilitating and progressive consequence of a wide range of upper motor neuron injuries that affect skeletal muscle function. One type of perinatal brain injury causes cerebral palsy (CP), which affects a child's ability to move and is often painful. While several rehabilitation therapies are used to treat contractures, their long-term effectiveness is marginal since such therapies do not change muscle biological properties. Therefore, new therapies based on a biological understanding of contracture development are needed. Here, we show that myoblast progenitors from contractured muscle in children with CP are hyperproliferative. This phenotype is associated with DNA hypermethylation and specific gene expression patterns that favor cell proliferation over quiescence. Treatment of CP myoblasts with 5-azacytidine, a DNA hypomethylating agent, reduced this epigenetic imprint to TD levels, promoting exit from mitosis and molecular mechanisms of cellular quiescence. Together with previous studies demonstrating reduction in myoblast differentiation, this suggests a mechanism of contracture formation that is due to epigenetic modifications that alter the myogenic program of muscle-generating stem cells. We suggest that normalization of DNA methylation levels could rescue myogenesis and promote regulated muscle growth in muscle contracture and thus may represent a new nonsurgical approach to treating this devastating neuromuscular condition.