Biology subjects

Konzman, D.

Publications and source records attributed to Konzman, D..

3 recordsLinked to original sources

bioRxiv2022

Activating and repressing gene expression between chromosomes during stochastic fate specification

DNA elements act across long genomic distances to regulate gene expression in processes including enhancer-promoter interactions and imprinting. During the gene-regulatory phenomenon of transvection in Drosophila, DNA elements on one allele of a gene act between chromosomes to increase or decrease expression of another allele of the gene. Despite the discovery of transvection over 60 years ago, little is known about its biological role. Furthermore, how different cis regulatory DNA elements contribute to the activation or repression of transvection at distinct times during development is unclear. Here, we studied the stochastic expression of spineless (ss) in developing photoreceptors in the fly eye to understand gene activation and repression between chromosomes. We identified a biological role for transvection in regulating expression of naturally occurring ss alleles. We characterized CRISPR-engineered deletions of sequences across the ss locus and identified DNA elements required for activating and repressing transvection. We found that different enhancers participated in transvection at different times during development to promote gene expression and specify cell fates. Bringing a silencer element on a heterologous chromosome into proximity with the ss locus "reconstituted" the gene, leading to repression. Our studies show that transvection regulates gene expression via distinct DNA elements at specific timepoints in development, with implications for genome organization and architecture.

developmental biology↗

bioRxiv2022

O-GlcNAc transferase plays a non-catalytic role in C. elegans male fertility

Animal behavior is influenced by the competing drives to maintain energy and to reproduce. The balance between these evolutionary pressures and how nutrient signaling pathways intersect with mating drive remains unclear. The nutrient sensor O-GlcNAc transferase, which post-translationally modifies intracellular proteins with a single monosaccharide, is responsive to cellular nutrient status and regulates diverse biological processes. Though essential in most metazoans, O-GlcNAc transferase (ogt-1) is dispensable in Caenorhabditis elegans, allowing genetic analysis of its physiological roles. Compared to control, ogt-1 males have a four-fold reduction in mean offspring, with nearly two thirds producing zero progeny. Interestingly, we found that isolated ogt-1 males are less likely to engage in mate-searching, and they initiate mating less often when exposed to mates. In addition, ogt-1 males which do initiate mating are less likely to continue with subsequent steps in the mating process, resulting in fewer successful sperm transfers. Lowering barriers to mating such as immobilizing mates or allowing more mating time significantly improves ogt-1 male mating. Surprisingly, we found high fertility levels for ogt-1 mutant males with hypodermal expression of wild-type ogt-1 and by ogt-1 harboring mutations that prevent the transfer of O-GlcNAc by OGT-1. This suggests OGT-1 serves a non-catalytic function in the hypodermis impacting the male mating drive. This study builds upon research on the nutrient sensor O- GlcNAc transferase and demonstrates a role it plays in the interplay between the evolutionary drives for reproduction and survival. Author SummaryAnimals must make decisions on whether to engage in reproduction or conserve energy. These decisions must take into account the energy available to the animal, therefore making the nutrient sensing enzyme OGT of particular interest. In response to nutrient levels in the cell, OGT transfers the GlcNAc sugar onto proteins to regulate their function. OGT is implicated in a number of human diseases including diabetes, cancer, and X-linked intellectual disability. By deleting the gene encoding OGT in the nematode C. elegans, we show OGT is required for male fertility. We assessed the behavior of these mutant male worms and found they have a reduced mating drive. Surprisingly, restoring OGT specifically in the hypodermis was able to raise male fertility and mating drive back to normal levels. In addition, missense mutations in the OGT catalytic domain which prevent the enzyme from transferring GlcNAc do not negatively impact fertility, suggesting a different function of OGT is important in this process. Our study demonstrates that OGT is important in critical behavioral decisions and that further investigation in C. elegans may help reveal new functions of the enzyme.

genetics↗

bioRxiv2020

Nutrient sensing pathways regulating adult reproductive diapause in C. elegans

Genetic and environmental manipulations, such as dietary restriction (DR), can improve both health span and lifespan in a wide range of organisms, including humans. Changes in nutrient intake trigger often overlapping metabolic pathways that can generate distinct or even opposite outputs depending on several factors, such as when DR occurs in the lifecycle of the organism or the nature of the changes in nutrients. Due to the complexity of metabolic pathways and the diversity in outputs, the underlying mechanisms regulating diet-associated pro-longevity are not yet well understood. Adult reproductive diapause (ARD) in the model organism Caenorhabditis elegans is a DR model that is associated with lengthened lifespan and reproductive potential (Angelo and Van Gilst 2009). As the metabolic pathways regulating ARD have not yet been explored in depth, we performed a candidate-based genetic screen analyzing select nutrient-sensing pathways to determine their contribution to the regulation of ARD. Focusing on the three phases of ARD (initiation, maintenance, and recovery), we find that ARD initiation is regulated by fatty acid metabolism, sirtuins, AMPK, and the O-linked N-acetyl glucosamine (O-GlcNAc) pathway. Although ARD maintenance was not significantly influenced by the nutrient sensors in our screen, we found that ARD recovery was modulated by energy sensing, stress response, insulin-like signaling, and the TOR pathway. We also discovered that fatty acid {beta}-oxidation regulates ARD initiation through a pathway involving the O-GlcNAc cycling enzyme, OGT-1, acting with the nuclear hormone receptor NHR-49. Consistent with these findings, our analysis revealed a change in levels of neutral lipids associated with ARD entry defects. Our findings thus identify novel conserved genetic pathways required for ARD entry and recovery and identify new genetic interactions that provide insight into the role of OGT and OGA.

genetics↗