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DOE OSTI2023

Transcriptomics of Temporal- versus Substrate-Specific Wood Decay in the Brown-Rot Fungus Fibroporia radiculosa

Brown-rot fungi lack many enzymes associated with complete wood degradation, such as lignin-attacking peroxidases, and have developed alternative mechanisms for rapid wood breakdown. To identify the effects of culture conditions and wood substrates on gene expression, we grew Fibroporia radiculosa in submerged cultures containing Wiley milled wood (5 days) and solid wood wafers (30 days), using aspen, pine, and spruce as a substrate. The comparative analysis revealed that wood species had a limited effect on the transcriptome: <3% of genes were differentially expressed between different wood species substrates. The comparison between gene expression during growth on milled wood and wood wafer conditions, however, indicated that the genes encoding plant cell wall-degrading enzymes, such as glycoside hydrolases and peptidases, were activated during growth on wood wafers, confirming previous reports. On the other hand, it was shown for the first time that the genes encoding Fenton chemistry enzymes, such as hydroquinone biosynthesis enzymes and oxidoreductases, were activated during submerged growth on ground wood. This illustrates the diversity of wood-decay reactions encoded in fungi and activated at different stages of this process.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2021

The soybean β‐expansin gene GmINS1 contributes to nodule development in response to phosphate starvation

Abstract Legume biological nitrogen fixation (BNF) is the most important N source in agricultural ecosystems. Nodule organogenesis from the primordia to the development of mature nodules with the ability to fix N 2 largely determines BNF capacity. However, nodule growth is often limited by low phosphorus (P) availability, while the mechanisms underlying nodule development responses to P deficiency remain largely unknown. In this study, we found that nodule enlargement is severely inhibited by P deficiency, as reflected by the smaller individual nodule size from a soybean core collection in the field. Wide‐ranging natural diversity in nodule size was further identified in soybeans reared in low P soils, with the FC‐1 genotype outperforming FC‐2 in assessments of nodulation under low P conditions. Among β‐expansin members, GmINS1 expression is most abundantly enhanced by P deficiency in FC‐1 nodules, and its transcript level is further displayed to be tightly associated with nodule enlargement. Four single nucleotide polymorphisms discovered in the GmINS1 promoter distinguished the FC‐1 and FC‐2 genotypes and accounted for the differential expression levels of GmINS1 responses to P deficiency. GmINS1 overexpression led to increases in nodule size, infected cell abundance, and N 2 fixation capacity and subsequently promoted increases in N and P content, soybean biomass, and yield. Our findings provide a candidate gene for optimizing BNF capacity responses to low P stress in soybean molecular breeding programs.

Yang, Zhaojun↗

DOE OSTI2023

JGI Plant Gene Atlas: an updateable transcriptome resource to improve functional gene descriptions across the plant kingdom

Abstract Gene functional descriptions offer a crucial line of evidence for candidate genes underlying trait variation. Conversely, plant responses to environmental cues represent important resources to decipher gene function and subsequently provide molecular targets for plant improvement through gene editing. However, biological roles of large proportions of genes across the plant phylogeny are poorly annotated. Here we describe the Joint Genome Institute (JGI) Plant Gene Atlas, an updateable data resource consisting of transcript abundance assays spanning 18 diverse species. To integrate across these diverse genotypes, we analyzed expression profiles, built gene clusters that exhibited tissue/condition specific expression, and tested for transcriptional response to environmental queues. We discovered extensive phylogenetically constrained and condition-specific expression profiles for genes without any previously documented functional annotation. Such conserved expression patterns and tightly co-expressed gene clusters let us assign expression derived additional biological information to 64 495 genes with otherwise unknown functions. The ever-expanding Gene Atlas resource is available at JGI Plant Gene Atlas (https://plantgeneatlas.jgi.doe.gov) and Phytozome (https://phytozome.jgi.doe.gov/), providing bulk access to data and user-specified queries of gene sets. Combined, these web interfaces let users access differentially expressed genes, track orthologs across the Gene Atlas plants, graphically represent co-expressed genes, and visualize gene ontology and pathway enrichments.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Transcript and metabolite network perturbations in lignin biosynthetic mutants of Arabidopsis

Abstract Lignin, one of the most abundant polymers in plants, is derived from the phenylpropanoid pathway, which also gives rise to an array of metabolites that are essential for plant fitness. Genetic engineering of lignification can cause drastic changes in transcription and metabolite accumulation with or without an accompanying development phenotype. To understand the impact of lignin perturbation, we analyzed transcriptome and metabolite data from the rapidly lignifying stem tissue in 13 selected phenylpropanoid mutants and wild-type Arabidopsis (Arabidopsis thaliana). Our dataset contains 20,974 expressed genes, of which over 26% had altered transcript levels in at least one mutant, and 18 targeted metabolites, all of which displayed altered accumulation in at least one mutant. We found that lignin biosynthesis and phenylalanine supply via the shikimate pathway are tightly co-regulated at the transcriptional level. The hierarchical clustering analysis of differentially expressed genes (DEGs) grouped the 13 mutants into 5 subgroups with similar profiles of mis-regulated genes. Functional analysis of the DEGs in these mutants and correlation between gene expression and metabolite accumulation revealed system-wide effects on transcripts involved in multiple biological processes.

Plant Sciences↗

DOE OSTI2020

RNA‐Seq analysis revealed the molecular mechanisms of photobiomodulation effect on human fibroblasts

Abstract Background The photobiomodulation (PBM) effect has been applied to various clinical therapy for a long time. However, the mechanism related to the PBM effect in terms of wavelengths has been lack of in‐depth study, except that ultraviolet radiation has attracted much attention due to its strong cell‐killing effect. Purpose To clarify the principle behind PBM and the main mechanism of improvement. Methods To carry on this study, we created light equipment using three LED chips, which emit 390 nm ultraviolet radiation, 415 nm blue light and 660 nm red light, respectively. We choose human fibroblasts (HF) to be irradiated by three different wavelengths for PBM test. In this study, we used cell counting kit (CCK‐8) test to show the cell proliferation roughly and reported on a systematic RNA sequencing (RNA‐seq) analysis at transcriptional expression levels from HF, which accepted PBM of different wavelengths of light. Results We found that 415 nm blue light inhibited cell proliferation and 660 nm red light stimulated cell proliferation while 390 nm ultraviolet radiation has little influence on cell proliferation. Furthermore, RNA‐seq results showed that CSF1R, PPP3CC, ITGAL, ITGAM, IL2RB, and several other differentially expressed genes (DEGs) are involved in the cell proliferation. Relative DEGs values for matrix metalloproteinases (MMPs) gene family have shown a great difference in blue and red light radiation especially on MMP25, MMP9, MMP21, and MMP13. Conclusion Taken together, the results provide a valuable resource to describe the variation of HFs under PBM of different light at gene level.

Li, Wenqi↗

DOE OSTI2021

NASA GeneLab RNA-seq consensus pipeline: Standardized processing of short-read RNA-seq data

With the development of transcriptomic technologies, we are able to quantify precise changes in gene expression profiles from astronauts and other organisms exposed to spaceflight. Members of NASA GeneLab and GeneLab-associated analysis working groups (AWGs) have developed a consensus pipeline for analyzing short-read RNA-sequencing data from spaceflight-associated experiments. The pipeline includes quality control, read trimming, mapping, and gene quantification steps, culminating in the detection of differentially expressed genes. This data analysis pipeline and the results of its execution using data submitted to GeneLab are now all publicly available through the GeneLab database. We present here the full details and rationale for the construction of this pipeline in order to promote transparency, reproducibility, and reusability of pipeline data; to provide a template for data processing of future spaceflight-relevant datasets; and to encourage cross-analysis of data from other databases with the data available in GeneLab.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Genome-Wide Study of Hsp90 Gene Family in Cabbage (Brassica oleracea var. capitata L.) and Their Imperative Roles in Response to Cold Stress

Heat shock protein 90 (Hsp90) plays an important role in plant developmental regulation and defensive reactions. Several plant species have been examined for the Hsp90 family gene. However, the Hsp90 gene family in cabbage has not been well investigated to date. In this study, we have been discovered 12 BoHsp90 genes in cabbage ( Brassica oleracea var. capitata L.). These B. oleracea Hsp90 genes were classified into five groups based on phylogenetic analysis. Among the five groups, group one contains five Hsp90 genes, including BoHsp90-1 , BoHsp90-2 , BoHsp90-6 , BoHsp90-10 , and BoHsp90-12 . Group two contains three Hsp90 genes, including BoHsp90-3 , BoHsp90-4 , and BoHsp90 . Group three only includes one Hsp90 gene, including BoHsp90-9 . Group four were consisting of three Hsp90 genes including BoHsp90-5 , BoHsp90-7 , and BoHsp90-8 , and there is no Hsp90 gene from B. oleracea in the fifth group. Synteny analysis showed that a total of 12 BoHsp90 genes have a collinearity relationship with 5 Arabidopsis genes and 10 Brassica rapa genes. The promoter evaluation revealed that the promoters of B. oleracea Hsp90 genes included environmental stress-related and hormone-responsive cis-elements . RNA-seq data analysis indicates that tissue-specific expression of BoHsp90-9 and BoHsp90-5 were highly expressed in stems, leaves, silique, and flowers. Furthermore, the expression pattern of B. oleracea BoHsp90 exhibited that BoHsp90-2, BoHsp90-3, BoHsp90-7, BoHsp90-9, BoHsp90-10, and BoHsp90-11 were induced under cold stress, which indicates these Hsp90 genes perform a vital role in cold acclimation and supports in the continual of normal growth and development process. The cabbage Hsp90 gene family was found to be differentially expressed in response to cold stress, suggesting that these genes play an important role in cabbage growth and development under cold conditions.

Sajad, Shoukat↗

DOE OSTI2023

Comparative transcriptome analysis of rainbow trout gonadal cells (RTG-2) infected with U and J genogroup infectious hematopoietic necrosis virus

Infectious hematopoietic necrosis virus (IHNV) is the causative pathogen of infectious hematopoietic necrosis, outbreaks of which are responsible for significant losses in rainbow trout aquaculture. Strains of IHNV isolated worldwide have been classified into five major genogroups, J, E, L, M, and U. To date, comparative transcriptomic analysis has only been conducted individually for the J and M genogroups. In this study, we compared the transcriptome profiles in U genogroup and J genogroup IHNV-infected RTG-2 cells with mock-infected RTG-2 cells. The RNA-seq results revealed 17,064 new genes, of which 7,390 genes were functionally annotated. Differentially expressed gene (DEG) analysis between U and J IHNV-infected cells revealed 2,238 DEGs, including 1,011 downregulated genes and 1,227 upregulated genes. Among the 2,238 DEGs, 345 new genes were discovered. The DEGs related to immune responses, cellular signal transduction, and viral diseases were further analyzed. RT-qPCR validation confirmed that the changes in expression of the immune response-related genes trpm2 , sting , itgb7 , ripk2 , and irf1 , cellular signal transduction-related genes irl , cacnb2 , bmp2l , gadd45α , and plk2 , and viral disease-related genes mlf1, mtor, armc5 , pik3r1 , and c-myc were consistent with the results of transcriptome analysis. Taken together, our findings provide a comprehensive transcriptional analysis of the differential virulence of the U and J genogroups of IHNV, and shed new light on the pathogenic mechanisms of IHNV strains.

Zhao, Jing-Zhuang↗

DOE OSTI2024

Longitudinal analysis of host protein serum signatures of treatment and recovery in pulmonary tuberculosis

A better understanding of treatment progression and recovery in pulmonary tuberculosis (TB) infectious disease is crucial. This study analyzed longitudinal serum samples from pulmonary TB patients undergoing interventional treatment to identify surrogate markers for TB-related outcomes. Serum that was collected at baseline and 8, 17, 26, and 52 weeks from 30 TB patients experiencing durable cure were evaluated and compared using a sensitive LC-MS/MS proteomic platform for the detection and quantification of differential host protein signatures relative to timepoint. The global proteome signature was analyzed for statistical differences across the time course and between disease severity and treatment groups. A total of 676 proteins showed differential expression in the serum over these timepoints relative to baseline. Comparisons to understand serum protein dynamics at 8 weeks, treatment endpoints at 17 and 26 weeks, and post-treatment at 52 weeks were performed. The largest protein abundance changes were observed at 8 weeks as the initial effects of antibiotic treatment strongly impacted inflammatory and immune modulated responses. However, the largest number of proteome changes was observed at the end of treatment time points 17 and 26 weeks respectively. Post-treatment 52-week results showed an abatement of differential proteome signatures from end of treatment, though interestingly those proteins uniquely significant at post-treatment were almost exclusively downregulated. Patients were additionally stratified based upon disease severity and compared across all timepoints, identifying 461 discriminating proteome signatures. These proteome signatures collapsed into discrete expression profiles with distinct pathways across immune activation and signaling, hemostasis, and metabolism annotations. Insulin-like growth factor (IGF) and Integrin signaling maintained a severity signature through 52 weeks, implying an intrinsic disease severity signature well into the post-treatment timeframe. Previous proteome studies have primarily focused on the 8-week timepoint in relation to culture conversion status. While this study confirms previous observations, it also highlights some differences. The inclusion of additional end of treatment and post-treatment time points offers a more comprehensive assessment of treatment progression within the serum proteome. Examining the expression dynamics at these later time periods will help in the investigation of relapse patients and has provided indicative markers of response and recovery.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2024

Transcriptomic Analysis of the CAM Species Kalanchoë fedtschenkoi Under Low- and High-Temperature Regimes

Temperature stress is one of the major limiting environmental factors that negatively impact global crop yields. Kalanchoë fedtschenkoi is an obligate crassulacean acid metabolism (CAM) plant species, exhibiting much higher water-use efficiency and tolerance to drought and heat stresses than C 3 or C 4 plant species. Previous studies on gene expression responses to low- or high-temperature stress have been focused on C 3 and C 4 plants. There is a lack of information about the regulation of gene expression by low and high temperatures in CAM plants. To address this knowledge gap, we performed transcriptome sequencing (RNA-Seq) of leaf and root tissues of K. fedtschenkoi under cold (8 °C), normal (25 °C), and heat (37 °C) conditions at dawn (i.e., 2 h before the light period) and dusk (i.e., 2 h before the dark period). Our analysis revealed differentially expressed genes (DEGs) under cold or heat treatment in comparison to normal conditions in leaf or root tissue at each of the two time points. In particular, DEGs exhibiting either the same or opposite direction of expression change (either up-regulated or down-regulated) under cold and heat treatments were identified. In addition, we analyzed gene co-expression modules regulated by cold or heat treatment, and we performed in-depth analyses of expression regulation by temperature stresses for selected gene categories, including CAM-related genes, genes encoding heat shock factors and heat shock proteins, circadian rhythm genes, and stomatal movement genes. Our study highlights both the common and distinct molecular strategies employed by CAM and C 3 /C 4 plants in adapting to extreme temperatures, providing new insights into the molecular mechanisms underlying temperature stress responses in CAM species.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2024

Comparing Transcriptomic Points of Departure to Apical Effect Concentrations For Larval Fathead Minnow Exposed to Chemicals with Four Different Modes Of Action

It is postulated that below a transcriptomic-based point of departure, adverse effects are unlikely to occur, thereby providing a chemical concentration to use in screening level hazard assessment. The present study extends previous work describing a high-throughput fathead minnow assay that can provide full transcriptomic data after exposure to a test chemical. One-day post-hatch fathead minnows were exposed to ten concentrations of three representatives of four chemical modes of action: organophosphates, ecdysone receptor agonists, plant photosystem II inhibitors, and estrogen receptor agonists for 24 h. Concentration response modeling was performed on whole body gene expression data from each exposure, using measured chemical concentrations when available. Transcriptomic points of departure in larval fathead minnow were lower than apical effect concentrations across fish species but not always lower than toxic effect concentrations in other aquatic taxa like crustaceans and insects. The point of departure was highly dependent on measured chemical concentration which were often lower than the nominal concentration. Differentially expressed genes between chemicals within modes of action were compared and often showed statistically significant overlap. In addition, reproducibility between identical exposures using a positive control chemical (CuSO 4 ) and variability associated with the transcriptomic point of departure using in silico sampling were considered. Results extend a transcriptomic-compatible fathead minnow high-throughput assay for possible use in ecological hazard screening.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2023

Influence of the irradiated pulmonary microenvironment on macrophage and T cell dynamics

The lung is sensitive to radiation, which increases the risk of normal tissue toxicity following radiation therapy. Adverse outcomes include pneumonitis and pulmonary fibrosis, which are thought to result from dysregulated intercellular communication within the pulmonary microenvironment. Macrophage accumulation in the lung following radiation exposure is implicated in these pathogenic outcomes. Here we investigate the role of the microenvironment in macrophage and T cell dynamics. Materials and methods C57Bl/6 mice received 6Gyx5 x-ray irradiation to the right lung. Macrophage and T cell dynamics were investigated in ipsilateral right lungs, contralateral left lungs and compared to those from non-irradiated control subjects at 4-26wk post exposure. Lungs were evaluated by flow cytometry, histology and proteomics. Results In uni-lung irradiated subjects, focal regions of macrophage accumulation were noted in both lungs by 8wk, however fibrotic lesions were observed only in ipsilateral lungs by 26wk. Both infiltrating and alveolar macrophages populations transiently expanded in both lungs, however a transitional CD11b+ alveolar macrophage population persisted only in ipsilateral lungs and expressed lower CD206. Concurrently, arginase-1+ macrophages were noted within areas of macrophage accumulation in ipsilateral but not contralateral lungs at 8 and 26wk post exposure, while CD206+ macrophages were absent from these accumulations. While CD8+ T cells were present in both lungs of irradiated subjects, T regulatory cells were only increased in ipsilateral lungs. Unbiased proteomics analysis of immune cells revealed a substantial number of differentially expressed proteins in ipsilateral lungs when compared to either contralateral or non-irradiated lungs, as well as between contralateral lungs from irradiated subjects and non-irradiated controls. Conclusions Pulmonary macrophage and T cell dynamics are impacted by the microenvironmental conditions that develop in the lung following radiation exposure, both locally and systemically. Our findings demonstrate that while macrophages and T cells infiltrate and expand in both lungs, they diverge phenotypically depending on their environment.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2025

Separate, separated, and together: the transcriptional program of the Clostridium acetobutylicum-Clostridium ljungdahlii syntrophy leading to interspecies cell fusion

ABSTRACT Syntrophic cocultures (hitherto assumed to be commensalistic) of Clostridium acetobutylicum and Clostridium ljungdahlii , whereby CO 2 and H 2 produced by the former feed the latter, result in interspecies cell fusion involving large-scale exchange of protein, RNA, and DNA between the two organisms. Although mammalian cell fusion is mechanistically dissected, the mechanism for such microbial-cell fusions is unknown. To start exploring this mechanism, we used RNA sequencing to identify genes differentially expressed in this coculture using two types of comparisons. One type compared coculture to the two monocultures, capturing the combined impact of interactions through soluble signals in the medium and through direct cell-to-cell interactions. The second type compared membrane-separated versus -unseparated cocultures, isolating the impact of interspecies physical contact. While we could not firmly identify specific genes that might drive cell fusion, consistent with our hypothesized model for this interspecies microbial cell fusion, we observed differential regulation of genes involved in C. ljungdahlii’s autotrophic Wood-Ljungdahl pathway metabolism and genes of the motility machinery. Unexpectedly, we also identified differential regulation of biosynthetic genes of several amino acids, and notably of arginine and histidine. We verified that they are produced by C. acetobutylicum and are metabolized by C. ljungdahlii to its growth advantage. These and other findings, and notably upregulation of C. acetobutylicum ribosomal-protein genes, paint a more complex syntrophic picture and suggest a mutualistic relationship, whereby beyond CO 2 and H 2 , C. acetobutylicum feeds C. ljungdahlii with growth-boosting amino acids, while benefiting from the H 2 utilization by C. ljungdahlii . IMPORTANCE The construction and study of synthetic microbial cocultures is a growing research area due to the untapped potential of defined multi-species industrial bioprocesses and the utility of defined cocultures for generating insight into complex, undefined, natural microbial consortia. Our previous work showed that coculturing C. acetobutylicum and C. ljungdahlii leads to a unique metabolic phenotype (production of isopropanol) and heterologous cell fusion events. Here, we used RNAseq to explore genes involved in and impacted by these fusions. First, we compared gene expression in coculture to each monoculture. Second, we utilized a transwell system to compare gene expression in mixed cocultures to cocultures with both species physically separated by a permeable membrane, isolating the impact of interspecies “touching” on the transcriptome. This study deepens our mechanistic understanding of the C. acetobutylicum-C. ljungdahlii coculture phenotype, laying the groundwork for reverse genetic studies of heterologous cell fusion in Clostridium cocultures.

Willis, Noah B. (ORCID:0009000689365955)↗

DOE OSTI2021

Age-associated expression of p21and p53 during human wound healing

In mice, cellular senescence and senescence-associated secretory phenotype (SASP) positively contribute to cutaneous wound healing. In this proof-of-concept study, we investigated the expressions of p16, p21, and other senescence-associated biomarkers during human wound healing in 24 healthy subjects using a double-biopsy experimental design. The first punch biopsy created the wound and established the baseline. The second biopsy, concentric to the first and taken several days after wounding, was used to probe for expression of biomarkers by immunohistochemistry and RNA FISH. To assess the effects of age, we recruited 12 sex-matched younger (30.2 ± 1.3 years) and 12 sex-matched older (75.6 ± 1.8 years) subjects. We found that p21 and p53, but not p16, were induced during healing in younger, but not older subjects. A role for Notch signaling in p21 expression was inferred from the inducible activation of HES1. Further, other SASP biomarkers such as dipeptidyl peptidase-4 (DPP4) were significantly induced upon wounding in both younger and older groups, whereas matrix metallopeptidase 9 (MMP9) was induced only in the younger group. Senescence-associated β-galactosidase (SA-β-gal) was not detectable before or after wounding. This pilot study suggests the possibility that human cutaneous wound healing is characterized by differential expression of p21 and p53 between younger and older subjects.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2024

Transcriptomic and metabolomic changes in postharvest sugarbeet roots reveal widespread metabolic changes in storage and identify genes potentially responsible for respiratory sucrose loss

Endogenous metabolism is primarily responsible for losses in sucrose content and processing quality in postharvest sugarbeet roots. The genes responsible for this metabolism and the transcriptional changes that regulate it, however, are largely unknown. To identify genes and metabolic pathways that participate in postharvest sugarbeet root metabolism and the transcriptional changes that contribute to their regulation, transcriptomic and metabolomic profiles were generated for sugarbeet roots at harvest and after 12, 40 and 120 d storage at 5 and 12°C and gene expression and metabolite concentration changes related to storage duration or temperature were identified. During storage, 8656 genes, or 34% of all expressed genes, and 225 metabolites, equivalent to 59% of detected metabolites, were altered in expression or concentration, indicating extensive transcriptional and metabolic changes in stored roots. These genes and metabolites contributed to a wide range of cellular and molecular functions, with carbohydrate metabolism being the function to which the greatest number of genes and metabolites classified. Because respiration has a central role in postharvest metabolism and is largely responsible for sucrose loss in sugarbeet roots, genes and metabolites involved in and correlated to respiration were identified. Seventy-five genes participating in respiration were differentially expressed during storage, including two bidirectional sugar transporter SWEET17 genes that highly correlated with respiration rate. Weighted gene co-expression network analysis identified 1896 additional genes that positively correlated with respiration rate and predicted a pyruvate kinase gene to be a central regulator or biomarker for respiration rate. Overall, these results reveal the extensive and diverse physiological and metabolic changes that occur in stored sugarbeet roots and identify genes with potential roles as regulators or biomarkers for respiratory sucrose loss.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2020

The role of mab‐3 in spermatogenesis and ontogenesis of pinewood nematode, Bursaphelenchus xylophilus

Abstract Background Bursaphelenchus xylophilus is one of the most destructive invasive species, causing extensive economic losses worldwide. The sex ratio of female to male of B. xylophilus plays an important role in the nematode infestation. However, little is known about the processes of its sex determination. The double sex/mab‐3‐related family of transcription factors are highly conserved in animals, playing crucial roles in sex determination, spermatogenesis and ontogenesis. We therefore investigated its orthologue, Bxy‐mab‐3 , in B. xylophilus . Results Bxy‐mab‐3 has two typical conserved DNA‐binding domains. It was observed in J2 (the second‐stage of juveniles), J3, J4 and male adults (specifically on the spicules), but not in eggs or female adults via mRNA in situ hybridization. RNA‐Seq indicated significantly higher expression in males. RNAi showed that the body size and sperm size of male adults were markedly smaller than those of the controls. Meanwhile, almost all the RNAi‐treated males failed to mate with the normal females, even 26.34% of interfered males did not produce sperm. However, RNAi of Bxy‐mab‐3 had no effect on the sex ratio of B. xylophilus . Conclusion Bxy‐mab‐3 is indispensable for spermatogenesis, ontogenesis and mating behavior. It is a typical sex‐determination gene with differential expression in males and females. However, knocking down Bxy‐mab‐3 expression could not alter the sex ratio as seen in other species. Our findings contribute towards a better understanding of the molecular events of Bxy‐mab‐3 in B. xylophilus , which provides promising hints for control of pine wilt disease by blocking ontogenesis and decreasing nematode fecundity.

Zhou, Lifeng↗

DOE OSTI2024

Simulated Microgravity Alters Gene Regulation Linked to Immunity and Cardiovascular Disease

Microgravity exposure induces a cephalad fluid shift and an overall reduction in physical activity levels which can lead to cardiovascular deconditioning in the absence of countermeasures. Future spaceflight missions will expose crew to extended periods of microgravity among other stressors, the effects of which on cardiovascular health are not fully known. In this study, we determined cardiac responses to extended microgravity exposure using the rat hindlimb unloading (HU) model. We hypothesized that exposure to prolonged simulated microgravity and subsequent recovery would lead to increased oxidative damage and altered expression of genes involved in the oxidative response. To test this hypothesis, we examined hearts of male (three and nine months of age) and female (3 months of age) Long–Evans rats that underwent HU for various durations up to 90 days and reambulated up to 90 days post-HU. Results indicate sex-dependent changes in oxidative damage marker 8-hydroxydeoxyguanosine (8-OHdG) and antioxidant gene expression in left ventricular tissue. Three-month-old females displayed elevated 8-OHdG levels after 14 days of HU while age-matched males did not. In nine-month-old males, there were no differences in 8-OHdG levels between HU and normally loaded control males at any of the timepoints tested following HU. RNAseq analysis of left ventricular tissue from nine-month-old males after 14 days of HU revealed upregulation of pathways involved in pro-inflammatory signaling, immune cell activation and differential expression of genes associated with cardiovascular disease progression. Taken together, these findings provide a rationale for targeting antioxidant and immune pathways and that sex differences should be taken into account in the development of countermeasures to maintain cardiovascular health in space.

Genetics & Heredity↗

DOE OSTI2021

The oncogenic role of meiosis-specific Aurora kinase C in mitotic cells

Highlights: • AURKC is expressed in meiotic cells and some cancers. • AURKC expression increases cell migration and transformation of human mitotic cells. • Deletion of AURKC in U2OS cells decreases cell migration and soft agar growth. • Transcriptome analysis reveals that AURKC alters the extracellular matrix. Aberrant expression of meiosis-specific genes in cancer has recently emerged as a driver of some cancer formation. Aurora kinase C (AURKC) is a member of the Aurora kinase family of proteins known to regulate chromosome segregation during cell divisions. AURKC is normally expressed in meiotic cells; however, elevated levels of AURKC mRNA and protein are frequently measured in cancer cells. To understand the function of AURKC in cancer cells, expression was induced in noncancerous, human retina pigmented epithelial cells. While AURKC expression did not alter cell proliferation over 72 h, it did increase cell migration and anchorage independent growth in soft agar suggesting an oncogenic role in mitotically dividing cells. To evaluate AURKC as a potential therapeutic target, a frameshift mutation in the gene was introduced in U2OS osteosarcoma cells using CRISPR-Cas9 technology resulting in a premature stop codon. Cancer cells lacking AURKC displayed no change in cell proliferation over 72 h but did migrate less and formed fewer colonies in soft agar. Whole transcriptome sequencing analysis uncovered over 400 differentially expressed genes in U2OS cells with and without AURKC. GO analysis revealed alterations in proteinaceous extracellular matrix genes including COL1A1. These data indicate that therapeutics targeting AURKC could decrease cancer cell metastasis and disease progression. Because AURKC is transcriptionally silenced in normal mitotic cells, its disruption could specifically target cancer cells limiting the toxic side effects associated with current therapeutics.

60 APPLIED LIFE SCIENCES↗