Biology subjects

Park, S. C.

Publications and source records attributed to Park, S. C..

9 recordsLinked to original sources

bioRxiv2026

LEO1 loss promotes ER stress-adapted migration and cholesterol dependency in colorectal cancer

The RNA polymerase-associated factor 1 complex (PAF1C) is an evolutionarily conserved transcription elongation complex that regulates RNA polymerase II-mediated transcription and chromatin modification. LEO1, a core subunit of PAF1C, has been implicated in developmental gene regulation, WNT signaling, and leukemogenesis; however, its role in solid tumor progression remains poorly understood. In this study, we found that although LEO1 expression is generally elevated in colorectal cancer (CRC), its expression is reduced in stage IV tumors and is associated with poor clinical outcomes. To investigate its function, we established LEO1 -deficient HCT116 cell line and performed transcriptomic analyses. Loss of LEO1 suppressed epithelial differentiation and developmental gene programs while inducing cell cycle delay. Despite these changes, LEO1-deficient cells exhibited aggressive phenotypes, including enlarged nuclei and increased expression of migration-associated genes, which were further enhanced under glucose deprivation. Motif analysis identified FOXM1 as a key regulator of these migration-related genes. Mechanistically, LEO1 deficiency promoted accelerated transcriptional activation of GRP78, a central regulator of endoplasmic reticulum (ER) stress adaptation. GRP78 was required for survival under ER stress conditions, and its inhibition suppressed both migration and migration-associated gene expression. In addition, transcriptomic analyses revealed upregulation of cholesterol metabolism-related genes in LEO1-deficient cells. Consistently, treatment with the HMG-CoA reductase inhibitor atorvastatin selectively impaired their survival, indicating cholesterol metabolic dependency. Collectively, these findings demonstrate that LEO1 loss promotes ER stress-adapted migration and cholesterol metabolic dependency in CRC, suggesting that these pathways may represent therapeutic vulnerabilities in metastatic LEO1-low CRC.

cancer biology↗

bioRxiv2026

Copper transport is required for metabolism and persistence of Toxoplasma gondii

Copper is a conserved cofactor, required for essential processes including aerobic respiration. Pathogens subvert host copper; however the mechanisms of copper uptake are not well understood. Here, we identify and validate two copper transporters of Toxoplasma gondii and determine the role of copper in parasite metabolism and pathogenesis. We show that Ctr1 is required for copper uptake. Deletion leads to undetectable parasite-associated copper, a significant growth defect and a metabolic shift from mitochondrial respiration with to glycolysis. Absence of Crt1 was fully and rapidly rescued by exogenous copper, which we believe is transported through the lower-affinity transporter Ctr2. Ctr2 is dispensable in rapid growth, however, has a role in parasite persistence in chronic infection, both in vitro and in vivo. Together, these findings reveal for the first time a critical role for copper uptake in shaping metabolic plasticity, and highlights the importance of nutrient availability in regulating apicomplexan metabolism.

cell biology↗

bioRxiv2024

Host cell-specific metabolism of linoleic acid controls Toxoplasma gondii growth in cell culture

The obligate intracellular parasite Toxoplasma gondii can infect and replicate in any warm-blooded cell tested to date, but much of our knowledge about T. gondii cell biology comes from just one host cell type: human foreskin fibroblasts (HFFs). To expand our knowledge of host-parasite lipid interactions, we studied T. gondii in intestinal epithelial cells, the first site of host-parasite contact following oral infection and the exclusive site of parasite sexual development in feline hosts. We found that highly metabolic Caco-2 cells are permissive to T. gondii growth even when treated with high levels of linoleic acid (LA), a polyunsaturated fatty acid (PUFA) that kills parasites in HFFs. Caco-2 cells appear to sequester LA away from the parasite, preventing membrane disruptions and lipotoxicity that characterize LA-induced parasite death in HFFs. Our work is an important step toward understanding host-parasite interactions in feline intestinal epithelial cells, an understudied but important cell type in the T. gondii life cycle.

microbiology↗

bioRxiv2023

Terpenoid balance in Aspergillus nidulans unveiled by heterologous squalene synthase expression

Filamentous fungi produce numerous uncharacterized natural products (NPs) that are often challenging to characterize due to cryptic expression in laboratory conditions. Previously, we have successfully isolated novel NPs by expressing fungal artificial chromosomes (FACs) from a variety of fungal species into Aspergillus nidulans. Here, we demonstrate a new twist to FAC utility wherein heterologous expression of a Pseudogymnoascus destructans FAC in A. nidulans altered endogenous terpene biosynthetic pathways. In contrast to wildtype, the FAC transformant produced increased levels of squalene and aspernidine type compounds, including three new nidulenes (1-2, 5), and lost nearly all ability to synthesize the major A. nidulans characteristic terpene, austinol. Deletion of a squalene synthase gene in the FAC restored wildtype chemical profiles. The altered squalene to farnesyl pyrophosphate ratio leading to synthesis of nidulenes and aspernidines at the expense of farnesyl pyrophosphate derived austinols provides unexpected insight into routes of terpene synthesis in fungi. TeaserReshaping terpenes: Heterologous FAC expression reroutes terpene pathways.

microbiology↗

bioRxiv2023

A network-based model of Aspergillus fumigatus elucidates regulators of development and defensive natural products of an opportunistic pathogen

Aspergillus fumigatus is a notorious pathogenic fungus responsible for various harmful, sometimes lethal, diseases known as aspergilloses. Understanding the gene regulatory networks that specify the expression programs underlying this fungus diverse phenotypes can shed mechanistic insight into its growth, development, and determinants of pathogenicity. We used eighteen RNA-seq datasets (seventeen publicly available and one previously unpublished) of Aspergillus fumigatus to construct a comprehensive gene regulatory network resource. Our resource, named GRAsp (Gene Regulation of Aspergillus fumigatus), was able to recapitulate known regulatory pathways such as response to hypoxia, iron and zinc homeostasis, and secondary metabolite synthesis. Further, GRAsp was experimentally validated in two cases: one in which GRAsp accurately identified an uncharacterized transcription factor negatively regulating the production of the virulence factor gliotoxin and another where GRAsp revealed the bZip protein, AtfA, as required for fungal responses to microbial signals known as lipo-chitooligosaccharides. Our work showcases the strength of using network-based approaches to generate new hypotheses about regulatory relationships in Aspergillus fumigatus. We also unveil an online, user-friendly version of GRAsp available to the Aspergillus research community.

systems biology↗

bioRxiv2023

Vutiglabridin Alleviates Cellular Senescence Process of Dysfunctional Replication, Metabolic Regulation, and Circadian Clock in Primary Human Dermal Fibroblasts

The process of cellular senescence, which is characterized by stable cell cycle arrest, is strongly associated with dysfunctional cellular metabolism and circadian rhythmicity, both of which are reported to result from and also be causal to cellular senescence. As a result, modifying any of them - senescence, metabolism, or the circadian clock - may affect all three simultaneously. Obesity accelerates aging by disrupting the homeostasis of reactive oxygen species (ROS) via an increased mitochondrial burden of fatty acid oxidation. As a result, if senescence, metabolism, and circadian rhythm are all linked, anti-obesity treatments may improve metabolic regulation while also alleviating senescence and circadian rhythm. Vutiglabridin is a small molecule in clinical trials that improves obesity by enhancing mitochondrial function. We found that chronic treatment of senescent primary human dermal fibroblasts (HDFs) with vutiglabridin alleviates all investigated markers of cellular senescence (SA-{beta}-gal, CDKN1A, CDKN2A) and dysfunctional cellular circadian rhythm (BMAL1), while remarkably preventing the alterations of mitochondrial function and structure that occur during the process of cellular senescence. Our results demonstrate the significant senescence-alleviating effects of vutiglabridin, specifically with the restoration of cellular circadian rhythmicity and metabolic regulation. These data support the potential development of vutiglabridin against aging-associated diseases and corroborate the intricate link between cellular senescence, metabolism, and the circadian clock.

physiology↗

bioRxiv2020

The instantaneous multi-pronged defense system of latex against general plant enemies

Based on the hypothesis that variation of the metabolomes of latex is a response to selective pressure and should thus be affected differently from other organs, their variation could provide insight into the defensive chemical selection of plants. Metabolic profiling was utilized to compare tissues of Euphorbia species collected in various regions. The metabolic variation of latexes was much more limited than that of other organs. In all of the species, the levels of polyisoprenes and terpenoids were found to be much higher in latexes than in leaves and roots. Polyisoprenes were also observed to physically delay the contact and growth of pathogens with plant tissues. A secondary barrier composed of terpenes and, in particular, 24-methylenecycloartanol, exhibited antifungal activity. These results, together with the known roles of the enzymes also present in latexes, demonstrate that they are part of a cooperative defense system that comprises both biochemical and physical elements.

ecology↗

bioRxiv2018

Uncovering the role admixture in health disparity: characterization of hepatocyte gene expression and DNA methylation in African-Americans

BackgroundAfrican Americans (AAs) are an admixed population with portions of their genome derived from West Africans and Europeans. In AAs, the proportion of West African ancestry (WAA) can vary widely and may explain the genetic drivers of disease, specifically those that disproportionately affect this understudied population. To examine the relationship between the proportion of WAA and gene expression, we used high dimensional data obtained from AA primary hepatocytes, a tissue important in disease and drug response. MethodsRNA sequencing (Illumina HiSeq Platform) was conducted on 60 AA-derived primary hepatocytes, with methylation profiling (Illumina MethylationEPIC BeadChip) of 44 overlapping samples. WAA for each sample was calculated using fastSTRUCTURE and correlated to both gene expression and DNA methylation. The GTEx consortium (n = 15) was used for replication and a second cohort (n = 206) was using used for validation using differential gene expression between AAs and European-Americans. ResultsWe identified 131 genes associated with WAA (FDR< 0.1), of which 28 gene expression traits were replicated (FDR<0.1) and enriched in angiogenesis and inflammatory pathways (FDR<0.1). These 28 replicated gene expression traits represented 257 GWAS catalog phenotypes. Among the PharmGKB pharmacogenes, VDR, PTGIS, ALDH1A1, CYP2C19 and P2RY1 were associated with WAA (p < 0.05) with replication of CYP2C19 and VDR in GTEx. Association of DNA methylation with WAA identified 1037 differentially methylated regions (FDR<0.05), with hypomethylated genes enriched in drug response pathways. Overlapping of differentially methylated regions with the 131 significantly correlated gene expression traits identified 5 genes with concordant directions of effect: COL26A1, HIC1, MKNK2, RNF135, SNAI1 and TRIM39. ConclusionsWe conclude that WAA contributes to variability in hepatic gene expression and DNA methylation with identified genes indicative of diseases disproportionately affecting AAs. Specifically, WAA-associated genes were linked to previously identified loci in cardiovascular disease (PTGIS, PLAT), renal disease (APOL1) and drug response (CYP2C19).

genomics↗

bioRxiv2018

Concentration-dependent reduction of planktonic- and biofilm-state Vibrio alginolyticus by the bacteriophage pVa-21

There is an increasing emergence of antibiotic-resistant Vibrio alginolyticus, a zoonotic pathogen that causes mass mortality in aquatic animals as well as human infection; therefore, there is a demand for alternatives to antibiotics for treatment and prevention of infections caused by this pathogen. One possibility is through the exploitation of bacteriophages. In the present study, the bacteriophage pVa-21 belonging to Myoviridae, was isolated and characterized as a candidate biocontrol agent against V. alginolyticus. Its morphology, host range and infectivity, growth characteristics, planktonic or biofilm lytic property, stability under various conditions, and genome were investigated. Its latent period and burst size were estimated to be approximately 70 min and 58 plaque-forming units/cell, respectively. In addition, phage pVa-21 could inhibit bacterial growth both in the planktonic and biofilm state. Furthermore, phylogenetic and genome analyses revealed that the phage is closely related to phiKZ-like phages and can be classified as a new member of the phiKZ-like phages that infect bacteria belonging to the family Vibrionaceae.

microbiology↗