Biology subjects

Wilson, R.

Publications and source records attributed to Wilson, R..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

A human cytotrophoblast-villous endothelium-fetal organ multi-cell model and the impact on gene and protein expression in placenta cytotrophoblast, fetal hepatocytes and fetal kidney epithelial cells

Appropriate fetal growth during pregnancy requires multi-directional communication from the maternal, placental and fetal systems. Disruption in any of these signaling arms can have deleterious consequences for fetal growth and initiate developmental adaptations within fetal tissues and organs that are associated with both short- and long-term morbidities. In this proof-of-concept translational, human cell model study we aimed to identify the impacts of altered trophoblast stress response mechanisms and human insulin-like 1 growth factor (hIGF1) nanoparticle gene therapy on gene and protein expression in fetal liver hepatocytes and fetal kidney epithelial cells. We utilized human cell lines: BeWo choriocarcinoma cells (trophoblast), Human Placental Micro-Vascular Endothelial Cells, and WRL68 (hepatocytes) or HEK293T/17 (kidney epithelium), in a co-culture model designed to mimic cytotrophoblast-villous endothelium-fetal organ communication. Trophoblast stress response mechanisms were increased by culturing BeWo cells in growth media without FBS. Stressed BeWo cells were also treated with a hIGF1 nanoparticle gene therapy known to mitigate cellular stress mechanisms. Stressed BeWo cells had increased expression of cellular stress mechanisms but not when IGF1 was over-expressed with a transient hIGF1 nanoparticle gene therapy. Stressed and Stressed+hIGF1 BeWo cells had increased expression of gluconeogenesis and glycolysis rate-limiting enzymes. Gene and protein expression in fetal liver and kidney cells was not impacted by increased trophoblast stress or hIGF1 nanoparticle gene therapy. In conclusion, our data demonstrated that cytotrophoblast under stress turn on mechanisms involved in glucose production. Whether this is reflected in vivo remains uninvestigated but may represent a placental compensation mechanism in complicated pregnancies.

cell biology↗

bioRxiv2025

Placenta hIGF1 nanoparticle treatment in guinea pigs mitigates fetal sex dependent FGR-associated effects on kidney structure and blood pressure-related signaling pathways

Fetal development in an adverse in utero environment significantly increases the risk of hypertension and cardiovascular disease. The kidneys play a pivotal role in the regulation of blood pressure and cardiovascular function, and perturbations in kidney structure and molecular profile are often demonstrated in offspring born fetal growth restricted (FGR). The aim of this study was to determine whether improving the in utero fetal growth environment with a placental nanoparticle gene therapy would ameliorate FGR-associated dysregulation of fetal kidney development. Using the guinea pig maternal nutrient restriction (MNR) model, we improved placenta efficiency and fetal weight following three placental administrations of a non-viral polymer-based nanoparticle gene therapy from mid-pregnancy (gestational day 35) until gestational day 52. The nanoparticle gene therapy transiently increased expression of human insulin-like growth factor 1 (hIGF1) in placenta trophoblast. Fetal kidney tissue was collected near-term at gestational day 60. Differences in kidney structure, glomeruli size and gene expression of extracellular matrix (ECM) remodeling and blood pressure regulation-related factors were demonstrated in sham-treated FGR fetuses but not observed in FGR fetuses who received placental hIGF1 nanoparticle treatment. We speculate that mitigating the FGR-associated changes in kidney architecture and molecular profiles might confer protection against increased susceptibility to aberrant kidney physiology in later-life. Overall, this work opens avenues for future research to assess the long-term impact of the placental hIGF1 nanoparticle gene therapy on cardiovascular function in offspring.

physiology↗

bioRxiv2025

Multiplex-edited mice recapitulate woolly mammoth hair phenotypes

The woolly mammoth (Mammuthus primigenius) possessed a thick woolly coat and other cold-adaptive traits that enabled survival in harsh arctic environments. Current de-extinction efforts focus on genetically modifying the closely related Asian elephant to express woolly mammoth traits. In this study, we establish a multiplex-edited mouse model with modifications in genes associated with hair morphology and lipid metabolism, enabling insights into traits involved in developing woolly hair textures. Our optimized workflows achieved high editing efficiencies and produced genetically modified mice with simultaneous editing of up to seven different genes. Selected modifications include loss-of-function mutations in Fgf5, Tgm3, and Fam83g, among others. The resulting mice display exaggerated hair phenotypes including curly, textured coats, and golden-brown hair. This study advances methods of rapid establishment of complex genetic models. These approaches inform de-extinction efforts and research involving the genetic basis of mammalian hair development.

genetics↗

bioRxiv2025

Effects of elevation and microclimatic temperatures on butterfly-flower interaction networks in a Mediterranean mountain range

O_LIResearching the properties of mutualistic networks over environmental gradients is a promising but underexplored means to test how global change can affect ecosystem assembly and functioning. We examined how elevation and microclimate influenced butterfly-flower interaction networks at the hottest time of year in a Mediterranean mountain range. C_LIO_LIThroughout July 2023, we recorded weekly butterfly-flower interaction networks from 36 transects in nine sites, across an 800 m elevation gradient in the Sierra de Guadarrama (Central Spain). We quantified the connectance, nestedness, modularity and robustness to species loss of networks, and related these descriptors using Generalized Additive Mixed Models to elevation, microclimate temperature (modelled using Microclima), date and time of day. C_LIO_LIThe networks were dominated at all sites by one or two abundant butterfly and flower species, but these varied with elevation. Butterfly networks were more robust to plant species loss at higher elevations, where communities showed increased linkage density. Butterfly-plant networks became less nested at higher microclimatic temperatures in July. Network properties also varied through the day, with connectance decreasing markedly from morning to afternoon. C_LIO_LIIn the Mediterranean mountains studied, summer butterfly-flower interaction networks were more resilient to disturbance at high elevations and in cooler microclimates. Nectar availability could become an important limiting factor for insects in a warming climate, and understanding the mechanisms influencing the properties of flower visitor networks is therefore likely to become increasingly important for adapting the conservation of insects to climate change. C_LI

ecology↗

bioRxiv2025

Placental Nutrient Transport and Signaling in a Guinea Pig Model of Fetal Growth Restriction with Repeated Placental Nanoparticle-mediated IGF1 Treatment

Roughly 10% of all pregnancies are affected by fetal growth restriction (FGR). The primary etiology of FGR is placental insufficiency: the placenta not providing the appropriate amount of nutrients and oxygen to the fetus. There is currently no treatment for FGR or placental insufficiency. Because of the placentas pivotal role in FGR and supplying nutrients to the fetus, it offers an excellent target for therapeutic intervention. Using a guinea pig maternal nutrient restriction model and a repeated placental nanoparticle-mediated IGF1 treatment, placental IGF1 signaling and nutrient transport pathways were characterized to understand changes with FGR and treatment. This study elucidates the signaling mechanisms in which repeated placental nanoparticle-mediated IGF1 treatment leads to correct fetal growth. Overall, this study resulted in sex-specific kinase signaling and nutrient transporter changes within the placenta in both FGR and treatment groups. Combined with our previous studies using this treatment, we demonstrate the basic molecular signaling of this treatment and recapitulate the plausibility of this therapy for future human translation.

molecular biology↗

bioRxiv2024

Alternative cGAS signaling promotes Herpes simplex encephalitis

During infection, foreign DNA is sensed by cyclic GMP-AMP synthase (cGAS) leading to the production of cGAMP, STING-dependent type I interferon and proinflammatory cytokine expression, and autophagy. To prevent a response to self-DNA, cGAS activity is tightly regulated. Dysregulation of cGAS underpins interferonopathies, such as Aicardi-Goutieres syndrome, as well as Lupus and neurodegenerative diseases like Parkinsons disease. Thus, cGAS and its product cGAMP are therapeutic targets. However, if cGAS functions independently of cGAMP signaling is undefined. Here, we identified an alternative signaling pathway that cGAS engages independent of cGAMP synthesis. We demonstrate that alternative cGAS signaling promotes hyperexpression of CXCL1 and enhanced neutrophil recruitment that facilitates viral dissemination during herpes simplex encephalitis. Our study is the first report of an alternative cGAS response independent of cGAMP highlighting a previously uncharacterized scaffold function for cGAS.

immunology↗

bioRxiv2024

Placental hIGF1 nanoparticle gene therapy in guinea pigs ameliorates fetal growth restriction-associated changes in hepatic lipid and glucose metabolism-related signaling pathways in a fetal sex-specific manner

Fetal development in an adverse in utero environment significantly increases the risk of developing metabolic diseases in later life, including dyslipidemia, non-alcoholic fatty liver diseases and diabetes. The aim of this study was to determine whether improving the in utero fetal growth environment with a placental nanoparticle gene therapy would ameliorate fetal growth restriction (FGR)-associated dysregulation of fetal hepatic lipid and glucose metabolism-related signaling pathways. Using the guinea pig maternal nutrient restriction (MNR) model of placental insufficiency and FGR, placenta efficiency was significantly improved following three administrations of a non-viral polymer-based nanoparticle gene therapy to the placenta from mid-pregnancy (gestational day 35) until gestational day 52. The nanoparticle gene therapy transiently increased expression of human insulin-like growth factor 1 (hIGF1) in placenta trophoblast. Fetal liver tissue was collected near-term at gestational day 60. Fetal sex specific differences in liver gene and protein expression of pro-fibrosis and glucose metabolism-related factors were demonstrated in sham-treated FGR fetuses but not observed in FGR fetuses who received placental hIGF1 nanoparticle treatment. Increased plasma bilirubin, and indirect measure of hepatic activity, was also increased with placental hIGF1 nanoparticle treatment. We speculate that the changes in liver gene and protein expression and increased liver activity that result in similar expression profiles to appropriately growing Control fetuses might confer protection against increased susceptibility to aberrant liver physiology in later-life. Overall, this work opens avenues for future research assessing the translational prospect of mitigating FGR-induced metabolic derangements. NEW AND NOTEWORTHYA placenta-specific non-viral polymer-based nanoparticle gene therapy that improves placenta nutrient transport and near-term fetal weight ameliorates growth restriction-associated changes to fetal liver activity, and cholesterol and glucose/nutrient homeostasis genes/proteins that might confer protection against increased susceptibility to aberrant liver physiology in later-life. This knowledge may have implications towards removing predispositions that increase the risk of metabolic diseases including diabetes, dyslipidemia and non-alcoholic fatty liver disease in later life.

physiology↗

bioRxiv2024

RIPK1 is essential for Herpes Simplex Virus-triggered ZBP1-dependent necroptosis in human cells

Necroptosis initiated by the host sensor Z-NA Binding Protein-1 (ZBP1) is essential for host defense against a growing number of viruses, including Herpes Simplex Virus-1 (HSV-1). Studies with HSV-1 and other necroptogenic stimuli in murine settings have suggested that ZBP1 triggers necroptosis by directly complexing with the kinase RIPK3. Whether this is also the case in human cells, or whether additional co-factors are needed for ZBP1-mediated necroptosis, is unclear. Here, we show that ZBP1-induced necroptosis in human cells requires RIPK1. We have found that RIPK1 is essential for forming a stable and functional ZBP1-RIPK3 complex in human cells, but is dispensable for the formation of the equivalent murine complex. The RIP Homology Interaction Motif (RHIM) in RIPK3 is responsible for this difference between the two species, because replacing the RHIM in human RIPK3 with the RHIM from murine RIPK3 is sufficient to overcome the requirement for RIPK1 in human cells. These observations describe a critical mechanistic difference between mice and humans in how ZBP1 engages in necroptosis, with important implications for treating human diseases.

cell biology↗

bioRxiv2024

Northern peatland microbial networks exhibit resilience to warming and acquire electron acceptor from soil organic matter

The microbial networks that regulate belowground carbon turnover and respond to climate change drivers in peatlands are poorly understood. Here, we leverage a whole ecosystem warming experiment to elucidate the key processes of terminal carbon decomposition and community responses to temperature rise. Our dataset of 697 metagenome-assembled genomes (MAGs) extends from surface (10 cm) to 2 m deep into the peat column, with only 3.7% of genomes overlapping with other well-studied peatlands. Unexpectedly, community composition has yet to show a significant response to warming after 3 years, suggesting that metabolically diverse soil microbial networks are resilient to climate change. Surprisingly, the dominant methanogens showed the potential for both acetoclastic and hydrogenotrophic methanogenesis. Nonetheless, the predominant pathways for anaerobic carbon decomposition include sulfate/sulfite reduction, denitrification, and acetogenesis, rather than methanogenesis based on gene abundances. Multi-omics data suggest that organic matter cleavage provides terminal electron acceptors, whichtogether with methanogen metabolic flexibility, may explain peat microbiome resilience to warming.

microbiology↗

bioRxiv2024

Mid-pregnancy placental transcriptome in a model of placental insufficiency with and without novel intervention

Fetal growth restriction (FGR) affects between 5-10% of all live births. Placental insufficiency is a leading cause of FGR, resulting in reduced nutrient and oxygen delivery to the fetus. Currently, there are no effective in utero treatment options for FGR, or placental insufficiency. We have developed a gene therapy to deliver, via a non-viral nanoparticle, human insulin-like 1 growth factor (hIGF1) to the placenta as potential treatment of placenta insufficiency and FGR. Using a guinea pig maternal nutrient restriction (MNR) model of FGR, we aimed to understand the transcriptional changes within the placenta associated with placental insufficiency that occur prior to/at initiation of FGR, and the impact of short-term hIGF1 nanoparticle treatment. Using RNAsequencing, we analyzed protein coding genes of three experimental groups: Control and MNR dams receiving a sham treatment, and MNR dams receiving hIGF1 nanoparticle treatment. Pathway enrichment analysis comparing differentially expressed genelists in sham-treated MNR placentas to Control revealed upregulation of pathways associated with degradation and repair of genetic information and downregulation of pathways associated with transmembrane transport. When compared to sham-treated MNR placentas, MNR + hIGF1 placentas demonstrated changes to genelists associated with transmembrane transporter activity including ion, vitamin and solute carrier transport. Overall, this study identifies the key signaling and metabolic changes occurring in the placenta contributing to placental insufficiency prior to/at initiation of FGR, and increases our understanding of the pathways that our nanoparticle-mediated gene therapy intervention regulates. Statements and DeclarationsO_ST_ABSCompeting InterestsC_ST_ABSAuthors declare no conflicts of interest.

physiology↗

bioRxiv2024

Maternal-fetal interfaces transcriptome changes associated with placental insufficiency and a novel gene therapy intervention

The etiology of fetal growth restriction (FGR) is multifactorial, although many cases often involve placental insufficiency. Placental insufficiency is associated with inadequate trophoblast invasion resulting in high resistance to blood flow, decreased availability of nutrients, and increased hypoxia. We have developed a non-viral, polymer-based nanoparticle that facilitates delivery and transient gene expression of human insulin-like 1 growth factor (hIGF1) in placental trophoblast for the treatment of placenta insufficiency and FGR. Using the established guinea pig maternal nutrient restriction (MNR) model of placental insufficiency and FGR, the aim of the study was to identify novel pathways in the sub-placenta/decidua that provide insight into the underlying mechanism driving placental insufficiency, and may be corrected with hIGF1 nanoparticle treatment. Pregnant guinea pigs underwent ultrasound-guided sham or hIGF1 nanoparticle treatment at mid-pregnancy, and sub-placenta/decidua tissue was collected 5 days later. Transcriptome analysis was performed using RNA Sequencing on the Illumina platform. The MNR sub-placenta/decidua demonstrated fewer maternal spiral arteries lined by trophoblast, shallower trophoblast invasion and downregulation of genelists involved in the regulation of cell migration. hIGF1 nanoparticle treatment resulted in marked changes to transporter activity in the MNR + hIGF1 sub-placenta/decidua when compared to sham MNR. Under normal growth conditions however, hIGF1 nanoparticle treatment decreased genelists enriched for kinase signaling pathways and increased genelists enriched for proteolysis indicative of homeostasis. Overall, this study identified changes to the sub-placenta/decidua transcriptome that likely result in inadequate trophoblast invasion and increases our understanding of pathways that hIGF1 nanoparticle treatment acts on in order to restore or maintain appropriate placenta function.

physiology↗

bioRxiv2024

Stop and go: exploring alternative mechanisms for task allocation in social insects - response and satisfaction thresholds trade off cost, accuracy, and speed differently

Division of labor, a key feature of many complex systems, requires a mechanism that allows individuals to choose tasks. The popular response threshold hypothesis posits that some workers start engaging in particular tasks at a lower level of need than others. However, individuals may only have access to information about need after they actually engage in a task. We therefore introduce two novel interpretations of this task-allocation mechanism. While the response threshold mechanism determines when individuals start working, the satisfaction threshold mechanism drives when individuals stop working. We also model a composite threshold mechanism where workers consider task need both to start and end working. Second, we model the possibility that the stimulus perceived by workers is a completion cue instead of a demand cue. While these may seem like subtle variations, we show here that they can yield dramatically different collective dynamics. In simulations with biologically relevant parameter ranges, response thresholds produced the quickest reaction to increases in task demand, satisfaction thresholds yielded the lowest task-switching rate, and composite thresholds most closely matched the number of workers allocated to the number needed. Different threshold types thus differentially trade off speed, cost, and accuracy. We did not model benefits of specialization; purely in terms of allocating workers to tasks, we also found that response thresholds usually perform worse than a null random choice model in terms of cost and efficiency, and variation among workers does not improve task allocation. Colonies utilizing task demand cues also tend to perform better than those using task completion cues. Our results ultimately suggest that different threshold mechanisms may be suited for different situations or types of tasks. Author SummaryDivision of labor is a phenomenon where workers in a community consistently differ in the tasks they work on. Many scientists believe division of labor arises in social insects (i.e. ants and bees) as a result of difference in workers responsiveness to cues that correspond to the demand for work in a task. For example, some ants in a colony start feeding brood much sooner than others, possibly because of a higher sensitivity, or lower response threshold, to brood pheromone. We show that instead of using such a cue to decide when to start on a task, theoretically workers may instead use it only to decide when to stop working; similarly, workers may use a cue that tells them how much work is needed in a task, or they may use one that corresponds to how much work has already been done. These seemingly subtle differences affect how much a colony invests in work and how quickly stability is reached when the balance of work needed in different tasks changes. Therefore, these different mechanisms may evolve to solve different problems.

animal behavior and cognition↗

bioRxiv2024

Nanoparticle-mediated delivery of placental gene therapy via uterine artery catheterization in a pregnant rhesus macaque

Nanoparticles offer promise as a mechanism to non-invasively deliver targeted placental therapeutics. Our previous studies utilizing intraplacental administration demonstrate efficient nanoparticle uptake into placental trophoblast cells and overexpression of human IGF1 (hIGF1). Nanoparticle-mediated placental overexpression of hIGF1 in small animal models of placental insufficiency and fetal growth restriction improved nutrient transport and restored fetal growth. The objective of this pilot study was to extend these studies to the pregnant nonhuman primate and develop a method for local delivery of nanoparticles to the placenta via maternal blood flow from the uterine artery. Nanoparticles containing hIGF1 plasmid driven by the placenta-specific PLAC1 promoter were delivered to a mid-gestation pregnant rhesus macaque via a catheterization approach that is clinically used for uterine artery embolization. Maternal-fetal interface, fetal and maternal tissues were collected four days post-treatment to evaluate the efficacy of hIGF1 treatment in the placenta. The uterine artery catheterization procedure and nanoparticle treatment was well tolerated by the dam and fetus through the four-day study period following catheterization. Nanoparticles were taken up by the placenta from maternal blood as plasmid-specific hIGF1 expression was detected in multiple regions of the placenta via in situ hybridization and qPCR. The uterine artery catheterization approach enabled successful delivery of nanoparticles to maternal circulation in close proximity to the placenta with no concerns to maternal or fetal health in this short-term feasibility study. In the future, this delivery approach can be used for preclinical evaluation of the long-term safety and efficacy of nanoparticle-mediated placental therapies in a rhesus macaque model. HighlightsNovel method to deliver therapeutics to maternal-fetal interface Delivery of nanoparticles to the placenta via maternal catheterization

physiology↗

bioRxiv2024

Placental Nanoparticle-mediated IGF1 Gene Therapy Corrects Fetal Growth Restriction in a Guinea Pig Model

Fetal growth restriction (FGR) caused by placental insufficiency is a major contributor to neonatal morbidity and mortality. There is currently no in utero treatment for placental insufficiency or FGR. The placenta serves as the vital communication, supply, exchange, and defense organ for the developing fetus and offers an excellent opportunity for therapeutic interventions. Here we show efficacy of repeated treatments of trophoblast-specific human insulin-like 1 growth factor (IGF1) gene therapy delivered in a non-viral, polymer nanoparticle to the placenta for the treatment of FGR. Using a guinea pig maternal nutrient restriction model (70% food intake) of FGR, nanoparticle-mediated IGF1 treatment was delivered to the placenta via ultrasound guidance across the second half of pregnancy, after establishment of FGR. This treatment resulted in correction of fetal weight in MNR + IGF1 animals compared to sham treated controls on an ad libitum diet, increased fetal blood glucose and decreased fetal blood cortisol levels compared to sham treated MNR, and showed no negative maternal side-effects. Overall, we show a therapy capable of positively impacting the entire pregnancy environment: maternal, placental, and fetal. This combined with our previous studies using this therapy at mid pregnancy in the guinea pig and in two different mouse model and three different human in vitro/ex vivo models, demonstrate the plausibility of this therapy for future human translation. Our overall goal is to improve health outcomes of neonates and decrease numerous morbidities associated with the developmental origins of disease.

physiology↗

bioRxiv2024

Heritable intraspecific variation among prey in size and movement interact to shape predation risk and potential natural selection

O_LIPredator and prey traits are important determinants of the outcomes of trophic interactions. In turn, the outcomes of trophic interactions shape the evolution of predator and prey traits. How species traits are likely to respond to selection from trophic interactions depends crucially on whether and how heritable species traits are and their genetic correlations. Of the many traits potentially influencing the outcomes of trophic interactions, body size and movement traits have emerged as universally key traits. Yet, how these traits shape and are shaped by trophic interactions is generally unclear, as few studies have simultaneously measured the impacts of these traits on the outcomes of trophic interactions, their heritability, and their correlations within the same system. C_LIO_LIWe used outcrossed and then clonally propagated lines of the ciliate protist Paramecium caudatum from natural populations to examine variation in morphology and movement behavior, the extent to which this variation was heritable, and how intraspecific differences among lines altered Paramecium susceptibility to predation by the copepod Macrocyclops albidus. C_LIO_LIWe found that the Paramecium lines exhibited heritable variation in body size and movement traits. In contrast to expectations from interspecific allometric relationships, body size and movement speed showed little covariance among clonal lines. The proportion of Paramecium consumed by copepods was positively associated with Paramecium body size and velocity, however, we also found evidence of an interaction such that greater velocities led to greater predation risk for large body-sized paramecia but did not alter predation risk for smaller body-sized paramecia. The proportion of paramecia consumed was not related to copepod body size. These patterns of predation risk and heritable trait variation in paramecia suggest that copepod predation may act as a selective force operating independently on movement and body size and generating the strongest selection against large, high-velocity paramecia. C_LIO_LIOur results illustrate how the interactions between ecology and genetics can shape the potential natural selection on prey traits through the outcomes of trophic interactions. Further simultaneous measures of predation outcomes, traits, and their quantitative genetic characteristics will provide insights into the evolutionary ecology of species interactions and their eco-evolutionary consequences. C_LI

ecology↗

bioRxiv2024

Kinases in motion: impact of protein and small molecule interactions on kinase conformations

Protein kinases act as central molecular switches in the control of cellular functions. Alterations in the regulation and function of protein kinases may provoke diseases including cancer. In this study we investigate the conformational states of such disease-associated kinases using the high sensitivity of the Kinase Conformation (KinCon)-reporter system. We [fi]rst track BRAF-kinase activity conformation changes upon melanoma drug binding. Second, we also use the KinCon reporter technology to examine the impact of regulatory protein interactions on LKB1-kinase tumor suppressor functions. Third, we explore the conformational dynamics of RIP-kinases in response to TNF-pathway activation and small molecule interactions. Finally, we show that CDK4/6 interactions with regulatory proteins alter conformations which remain unaffected in the presence of clinically applied inhibitors. Apart from its predictive value, the KinCon technology helps to identify cellular factors that impact drug efficacies. The understanding of the structural dynamics of full-length protein kinases when interacting with small molecule inhibitors or regulatory proteins is crucial for designing more effective therapeutic strategies.

biochemistry↗

bioRxiv2023

AePUb promoter length modulates gene expression in Aedes aegypti

Molecular tools for modulating transgene expression in Aedes aegypti are few. Here we demonstrate that adjustments to the AePUb promoter length can alter expression levels of two reporter proteins in Ae. aegypti cell culture and in mosquitoes. This provides a simple means for increasing or decreasing expression of a gene of interest and easy translation from cells to whole insects.

molecular biology↗

bioRxiv2023

Chronic cisplatin exposure does not affect epimutations in C. elegans but induces fluctuations in tRNA-derived small non-coding RNAs.

The individual lifestyle and environment of an organism can influence its phenotype and potentially the phenotype of its offspring. The different genetic and non-genetic components of the inheritance system and their mutual interactions are key mechanisms to generate inherited phenotypic changes. Epigenetic changes can be transmitted between generations independently from changes in DNA sequence. In C. elegans, epigenetic differences, i.e., epimutations, mediated by small non-coding RNAs, particularly 22G-RNAs, as well as chromatin have been identified and their average persistence is 3 to 5 generations. In addition, previous research showed that some epimutations had a longer duration and concerned genes that were enriched for multiple components of xenobiotic response pathways. These results raise the possibility that environmental stresses might change the rate at which epimutations occur, with potential significance for adaptation. In this work, we explore this question by propagating C. elegans lines either in control conditions or in moderate or high doses of cisplatin, which introduces genotoxic stress by damaging DNA. Our results show that cisplatin has a limited effect on global small non-coding RNAs epimutations and epimutations in gene expression levels. However, cisplatin exposure leads to increased fluctuations in the levels of small non-coding RNAs derived from tRNA cleavage. We show that changes in tRNA-derived small RNAs may be associated with gene expression changes. Our work shows that epimutations are not substantially altered by cisplatin exposure but identifies transient changes in tRNA-derived small RNAs as a potential source of transcriptional variation induced by genotoxic stress.

molecular biology↗