miR-1 sustains muscle physiology by controlling V-ATPase complex assembly.

Muscle function requires unique structural and metabolic adaptations that can render muscle cells selectively vulnerable, with mutations in some ubiquitously expressed genes causing myopathies but sparing other tissues. We uncovered a muscle cell vulnerability by studying miR-1, a deeply conserved, muscle-specific microRNA whose ablation causes various muscle defects. Using Caenorhabditis elegans, we found that miR-1 represses multiple subunits of the ubiquitous vacuolar adenosine triphosphatase (V-ATPase) complex, which is essential for internal compartment acidification and metabolic signaling. V-ATPase subunits are predicted miR-1 targets in animals ranging from C. elegans to humans, and we experimentally validated this in Drosophila. Unexpectedly, up-regulation of V-ATPase subunits upon miR-1 deletion causes reduced V-ATPase function due to defects in complex assembly. These results reveal V-ATPase assembly as a conserved muscle cell vulnerability and support a previously unknown role for microRNAs in the regulation of protein complexes.

Metabolic decisions in development and disease-a Keystone Symposia report.

There is an increasing appreciation for the role of metabolism in cell signaling and cell decision making. Precise metabolic control is essential in development, as evident by the disorders caused by mutations in metabolic enzymes. The metabolic profile of cells is often cell-type specific, changing as cells differentiate or during tumorigenesis. Recent evidence has shown that changes in metabolism are not merely a consequence of changes in cell state but that metabolites can serve to promote and/or inhibit these changes. Metabolites can link metabolic pathways with cell signaling pathways via several mechanisms, for example, by serving as substrates for protein post-translational modifications, by affecting enzyme activity via allosteric mechanisms, or by altering epigenetic markers. Unraveling the complex interactions governing metabolism, gene expression, and protein activity that ultimately govern a cell's fate will require new tools and interactions across disciplines. On March 24 and 25, 2021, experts in cell metabolism, developmental biology, and human disease met virtually for the Keystone eSymposium, "Metabolic Decisions in Development and Disease." The discussions explored how metabolites impact cellular and developmental decisions in a diverse range of model systems used to investigate normal development, developmental disorders, dietary effects, and cancer-mediated changes in metabolism.

Combinatorial Action of Temporally Segregated Transcription Factors.

Combinatorial action of transcription factors (TFs) with partially overlapping expression is a widespread strategy to generate novel gene-expression patterns and, thus, cellular diversity. Known mechanisms underlying combinatorial activity require co-expression of TFs within the same cell. Here, we describe the mechanism by which two TFs that are never co-expressed generate a new, intersectional expression pattern in C. elegans embryos: lineage-specific priming of a gene by a transiently expressed TF generates a unique intersection with a second TF acting on the same gene four cell divisions later; the second TF is expressed in multiple cells but only activates transcription in those where priming occurred. Early induction of active transcription is necessary and sufficient to establish a competent state, maintained by broadly expressed regulators in the absence of the initial trigger. We uncover additional cells diversified through this mechanism. Our findings define a mechanism for combinatorial TF activity with important implications for generation of cell-type diversity.