Jacobson, D. J. | Search bioRxiv

bioRxiv2024

Atf4 protects islet beta-cell identity and function under acute glucose-induced stress but promotes beta-cell failure in the presence of free fatty acid

Glucolipotoxicity, caused by combined hyperglycemia and hyperlipidemia, results in {beta}-cell failure and type 2 diabetes (T2D) via cellular stress-related mechanisms. Activating transcription factor 4 (Atf4) is an essential effector of stress response. We show here that Atf4 expression in {beta}-cells is dispensable for glucose homeostasis in young mice, but it is required for {beta}-cell function during aging and under obesity-related metabolic stress. Henceforth, aged Atf4-deficient {beta}-cells display compromised secretory function under acute hyperglycemia. In contrast, they are resistant to acute free fatty acid-induced loss-of identity and dysfunction. At molecular level, Atf4-deficient {beta}-cells down-regulate genes involved in protein translation, reducing {beta}-cell identity gene products under high glucose. They also upregulate several genes involved in lipid metabolism or signaling, likely contributing to their resistance to free fatty acid-induced dysfunction. These results suggest that Atf4 activation is required for {beta}-cell identity and function under high glucose, but this paradoxically induces {beta}-cell failure in the presence of high levels of free fatty acids. Different branches of Atf4 activity could be manipulated for protecting {beta}-cells from metabolic stress-induced failure. HighlightsO_LIAtf4 is dispensable in {beta}-cells in young mice C_LIO_LIAtf4 protects {beta}-cells under high glucose C_LIO_LIAtf4 exacerbate fatty acid-induced {beta}-cell defects C_LIO_LIAtf4 activates translation but depresses lipid-metabolism C_LI

genetics↗

bioRxiv2020

An introgressed gene causes meiotic drive in Neurospora sitophila

Meiotic drive elements cause their own preferential transmission following meiosis. In fungi this phenomenon takes the shape of spore killing, and in the filamentous ascomycete Neurospora sitophila, the Sk-1 spore killer element is found in many natural populations. In this study, we identify the gene responsible for spore killing in Sk-1 by generating both long and short-read genomic data and by using these data to perform a genome wide association test. Through molecular dissection, we show that a single 405 nucleotide long open reading frame generates a product that both acts as a poison capable of killing sibling spores and as an antidote that rescues spores that produce it. By phylogenetic analysis, we demonstrate that the gene is likely to have been introgressed from the closely related species N. hispaniola, and we identify three subclades of N. sitophila, one where Sk-1 is fixed, another where Sk-1 is absent, and a third where both killer and sensitive strain are found. Finally, we show that spore killing can be suppressed through an RNA interference based genome defense pathway known as meiotic silencing by unpaired DNA. Spk-1 is not related to other known meiotic drive genes, and similar sequences are only found within Neurospora. These results shed new light on the diversity of genes capable of causing meiotic drive, their origin and evolution and their interaction with the host genome. Significance StatementIn order to survive, most organisms have to deal with parasites. Such parasites can be other organisms, or sometimes, selfish genes found within the host genome itself. While much is known about parasitic organisms, the interaction with their hosts and their ability to spread within and between species, much less is known about selfish genes. We here identify a novel selfish "spore killer" gene in the fungus Neurospora sitophila. The gene appears to have evolved within the genus, but has entered the species through hybridization and introgression. We also show that the host can counteract the gene through RNA interference. These results shed new light on the diversity of selfish genes in terms of origin, evolution and host interactions.

evolutionary biology↗