Biology subjects

Takemon, Y.

Publications and source records attributed to Takemon, Y..

9 recordsLinked to original sources

bioRxiv2026

Aneuploidy sensitizes cells to SREBP-pathway inhibition in squamous cell carcinoma

Squamous cell carcinomas (SCCs) in the lung, head and neck, cervix, and esophagus are characterized by widespread chromosome-arm aneuploidies, most frequently recurrent 3q-gain. However, how these alterations influence cancer development and therapeutic vulnerabilities remains unclear. To identify aneuploidy-driven therapeutic targets, we performed genome-wide CRISPR interference (CRISPRi) and drug-repurposing screens in isogenic immortalized lung epithelial cells harboring chromosome 3-disomy or 3q-gain. Both screens converged on a mevalonate pathway dependency specific to 3q-gain cells, which exhibited heightened sensitivity to sterol regulatory element-binding protein (SREBP) disruption. Rescue experiments demonstrated that these vulnerabilities were on target and that pathway inhibition preferentially causes apoptosis in 3q-gain cells. Transcriptomic and lipidomic profiling revealed 3q-gain-associated alterations in SREBP activation, cholesterol and fatty-acid biosynthesis, and lipid composition. Perturbing SREBP signaling impaired viability in SCC cell lines and suppressed tumor growth in xenografts with 3q-gain. These findings identify an aneuploidy-driven, targetable vulnerability in SCC. SignificanceHere, we demonstrate that SCC-recurrent 3q-gain is a selective vulnerability to SREBP-pathway inhibition. We identify an aneuploidy-driven therapeutic liability in squamous tumors for lipid-targeted precision therapies, providing a framework for targeted treatment in SCC.

cancer biology↗

bioRxiv2024

Mapping in silico genetic networks of the KMT2D tumour suppressor gene to uncover novel functional associations and cancer cell vulnerabilities

Loss-of-function (LOF) alterations in tumour suppressor genes cannot be directly targeted. Approaches characterising gene function and vulnerabilities conferred by such mutations are required. Here, we computationally map genetic networks of KMT2D, a tumour suppressor gene frequently mutated in several cancer types. Using KMT2D loss-of-function (KMT2DLOF) mutations as a model, we illustrate the utility of in silico genetic networks in uncovering novel functional associations and vulnerabilities in cancer cells with LOF alterations affecting tumour suppressor genes. We revealed genetic interactors with functions in histone modification, metabolism, and immune response, and synthetic lethal (SL) candidates, including some encoding existing therapeutic targets. Analysing patient data from The Cancer Genome Atlas and the Personalized OncoGenomics Project, we showed, for example, elevated immune checkpoint response markers in KMT2DLOF cases, possibly supporting KMT2DLOF as an immune checkpoint inhibitor biomarker. Our study illustrates how tumour suppressor gene LOF alterations can be exploited to reveal potentially targetable cancer cell vulnerabilities.

bioinformatics↗

bioRxiv2022

The influence of river discharge on gravel bar hyporheic microbial community structure and putative metabolic functions.

O_LIMicrobial communities in the hyporheic zone (HZ) are important in self-purification as the riverbed is metabolically active and responsible for the retention, storage and mineralisation of organic matter transported to the surface water. However, studies exploring HZ microbial community responses to disturbances (e.g. floods) remain scarce. C_LIO_LIHere, we characterised the microbial community structure among the three (downwelling, upwelling and intermediate) HZ points within and among gravel bars at high and low discharge levels in a dam-regulated river using 16S rRNA metabarcoding. C_LIO_LIWe observed significant dissimilarity in the microbial community at low discharge exhibiting local adaptation due to gravel bar spatial environmental heterogeneity. Moreover, the homogenisation effect resulted in similar microbial community structures among the three points within the gravel bars at high discharge. Microbial communities across adjacent gravel bars were dissimilar, potentially attributing to different bar morphologies. C_LIO_LIOur study highlights the role of spatial environmental heterogeneity in the biological processes that govern microbial community structure at three hyporheic points in gravel bars at two discharge levels. C_LIO_LIOur results are essential to understand the HZ microbial communities response to the river discharge levels. C_LI

evolutionary biology↗

bioRxiv2022

GRETA: an R package for mapping in silico genetic interaction and essentiality networks

SummaryMapping genetic interaction and essentiality networks in human cell lines have been used to identify vulnerabilities of cells carrying specific genetic alterations and to associate novel functions to genes, respectively. In vitro and in vivo genetic screens to decipher these networks are resource-intensive, limiting the throughput of samples that can be analyzed. In this application note, we provide an R package we call Genetic inteRaction and EssentialiTy mApper (GRETA). GRETA is an accessible tool for in silico genetic interaction screens and essentiality network analyses using publicly available data, requiring only basic R programming knowledge. Availability and implementationThe R package, GRETA, is licensed under GNU General Public License v3.0 and freely available at https://github.com/ytakemon/GRETA and https://doi.org/10.5281/zenodo.6940757, with documentation and tutorial. A Singularity container is also available at https://cloud.sylabs.io/library/ytakemon/greta/greta. Contactmmarra@bcgsc.ca Supplemental informationSupplemental materials are available at Bioinformatics online. Issue sectionSystems biology

bioinformatics↗

bioRxiv2021

Implications of taxonomic and numerical resolution on DNA metabarcoding-based inference of benthic macroinvertebrate responses to river restoration

Exploring and clearly defining the level of taxonomic identification and quantification approaches for diversity and biomonitoring studies are essential, given its potential influence on the assessment and interpretation of ecological outcomes. In this study, we evaluated the response of benthic macroinvertebrate communities to the restoration or construction of gravel bars conducted in the dam-impacted Trinity River, with the non-dam influenced tributaries serving as the reference sites. We aim to evaluate the performance of different taxonomic and numerical (i.e., abundance vs. presence/absence data) resolutions of DNA metabarcoding with consequent comparison to morphology-based identification and how it affects assessment outcomes. DNA metabarcoding detected 93% of the morphologically identified individuals and provided finer taxonomic resolution. We also detected significant correlations between morphological sample abundance, biomass, and DNA metabarcoding read abundance. We observed a relatively high and significant congruence in macroinvertebrate community structure and composition between different taxonomic and numerical resolutions of both methods, indicating a satisfactory surrogacy between the two approaches and their varying identification levels and data transformation. Additionally, the community-environmental association were significant for all datasets but showed varying significant associations against the physicochemical parameters. Furthermore, both methods identified Simulium spp. as significant indicators of the dam-impacted gravel bars. Still, only DNA metabarcoding showed significant false discovery rate proving the methods robustness compared to morphology-based identification. Our observations imply that coarser taxonomic resolution could be highly advantageous to DNA metabarcoding-based applications in situations where the lack of taxonomic information, e.g., poor reference database, might severely affect the quality of biological assessments.

ecology↗

bioRxiv2020

Proteomic and transcriptomic profiling reveal different aspects of aging in the kidney

The kidney is an excellent model for studying organ aging. Kidney function shows steady decline with age and is easy to assay using urine or blood samples. However, little is known about the molecular changes that take place in the kidney during the aging process. In order to better understand the molecular changes that occur with age, we measured mRNA and protein levels in 188 genetically diverse mice at ages 6, 12, and 18 months. We observed distinctive change in mRNA and protein levels as a function of age. Changes in both mRNA and protein are associated with increased immune infiltration and decreases in mitochondrial function. Proteins show a greater extent of change and reveal changes in a wide array of biological processes including unique, organ-specific features of aging in kidney. Most importantly, we observed functionally important age-related changes in protein that occur in the absence of corresponding changes in mRNA. Our findings suggest that mRNA profiling alone provides an incomplete picture of molecular aging in the kidney and that examination of changes in proteins is essential to understand aging processes that are not transcriptionally regulated.

systems biology↗

bioRxiv2020

Profiling the microbial community structure and functional diversity of a dam-regulated river undergoing gravel bar restoration

BackgroundRiver restoration efforts are expected to influence and change the diversity and functions of microbial communities following the recovery of habitat characteristics in the river ecosystem. The recreation or restoration of gravel bars in the Trinity River in California aims to rehabilitate the environmental heterogeneity downstream of the dam impounded channel. Here, we profiled the community composition, estimated diversity, and annotated putative metabolic functions of the sediment microbial communities to assess whether the construction and restoration of gravel bars in the Trinity River in California enhanced environmental heterogeneity, with the increase in the microbial beta diversity of these in-channel structures against the free-flowing reach of the main channel with comparison to its undisturbed tributaries. ResultsMicrobial community composition of the free-flowing (i.e., no gravel bars) communities were relatively closer regardless of dam influence, whereas the Trinity River gravel bar and tributaries gravel bar communities were highly dissimilar. Proteobacteria, Bacteroidetes, and Acidobacteria were the highly abundant sediment microbial phyla on most sites, specifically in the Trinity River gravel bar communities. Putative functional annotation of microbial taxa revealed that chemoheterotrophy and aerobic chemoheterotrophy were the most prevalent microbial processes, with the Trinity River gravel bars having relatively higher representations. The considerably large abundance of heterotrophic taxa implies that gravel bars provide suitable areas for heterotrophic microorganisms with metabolic functions contributing to the net respiration in the river. ConclusionsOur results provide supporting evidence on the positive impact of habitat restoration being conducted in the Trinity River with the non-dam influenced, undisturbed tributaries as the basis of comparison. Gravel bar recreation and restoration contributed to the increased microbial biodiversity through the restoration of environmental heterogeneity at the river scale. We provided valuable insights into the potential microbial processes in the sediment that might be contributing to the biogeochemical processes carried out by the microbial communities in the Trinity River. The significant positive correlation between the functional diversity of the identified microbial taxa and beta diversity suggests that differences in the detected metabolic functions were closely related to dissimilarities in community composition.

microbiology↗

bioRxiv2019

Spatially Varying Trophic Effects of Reservoir-Derived Plankton on Stream Macroinvertebrates Among Heterogeneous Habitats Within Reaches

O_LIDam reservoirs often supply high amounts of plankton to downstream reaches, leading to a critical shift of trophic origins of stream ecosystems from natural sources (e.g. attached algae and terrestrial inputs) to reservoir-oriented plankton. Although this is a widely observed phenomenon, previous studies focused only on lotic habitats (e.g. riffles) rather than lentic habitats such as backwaters and isolated ponds (IP). C_LIO_LIUsing a stable isotope three-source mixing model, we evaluated trophic contributions of reservoir-derived plankton, epilithon and terrestrial leaves to stream macroinvertebrates at four dam outlet reaches and two reference reaches in the Natori River catchment, Japan. We compared four different habitat types co-occurring within the reaches: lotic habitat (riffle and pool), bar-head (BH) lentic habitat, bar-tail (BT) lentic habitat (backwater) and isolated pond (IP) on sandy bars. C_LIO_LIThe trophic contributions of reservoir-derived plankton were significantly lower in lentic habitats (BH, 15.4%; BT, 10.4%; IP, 9.1%) than in lotic habitats (mean, 27.7%). This was especially notable for filter feeders that feed on suspended fine particulate organic matter (SFPOM). The three-source model analysis indicated a lower biomass proportion of dam plankton in lentic SFPOM (mean, 21.2%) than in lotic SFPOM (mean, 35.6%). This difference in SFPOM composition was reflected in the lower trophic contribution of dam plankton to lentic filter feeders. C_LIO_LIThe abundance ratio of filter feeders in the community was decreased in lentic habitats, while the abundance ratios of collector-gatherers, scrapers and shredders were increased. Macroinvertebrates in lentic habitats fed on sources less mixed with reservoir-derived plankton (e.g. benthic coarse particulate organic matter [BCPOM], benthic fine particulate organic matter [BFPOM] and epilithon); therefore, the trophic impact of reservoirs was indistinctive at the community level, indicating that lentic habitats can function as trophic refugia to mitigate the trophic impact of reservoirs. C_LIO_LIBecause lentic habitats were decreased in area (accounting for 5.7% of average total area) in the downstream reaches of dams due to riverbed degradation, lentic habitats must be created in order to restore the trophic impact of reservoirs in river ecosystems. C_LI

ecology↗

bioRxiv2019

Spatial and phylogenetic structure of DNA-species of Alpine stonefly community assemblages across seven habitats

O_LIStream ecosystems are spatially heterogeneous, with many different habitat patches distributed within a small area. The influence of this heterogeneity on the biodiversity of benthic insect communities is well documented; however, studies of the role of habitat heterogeneity in species coexistence and community assembly remain limited. Here, we investigated how habitat heterogeneity influences spatial structure (beta biodiversity) and phylogenetic structure (evolutionary processes) of benthic stonefly (Plecoptera, Insecta) communities. C_LIO_LIWe sampled 20 sites along two Alpine rivers, including seven habitats in four different reaches (headwaters, meandering, bar-braided floodplain, and lowland spring-fed). We identified 21 morphological species and delineated 52 DNA-species based on sequences from mitochondrial cox1 and nuclear ITS markers. Using DNA-species, we first analysed the patterns of variation in richness, diversity, and community composition by quantifing the contribution of each of the four reaches and seven habitats to the overall DNA-species diversity using an additive partition of species diversity analysis and distance-based redundancy analysis. Using gene-tree phylogenies, we assessed whether environmental filtering led to the co-occurrence of DNA-species using a two-step analysis to find a phylogenetic signal. C_LIO_LIThe four reaches significantly contributed to DNA-species richness; with the meandering section having the highest contribution. However, we found that habitats had an effect on DNA-species diversity, where glide, riffle and, pool influenced the spatial structure of stonefly communities possibly due to a high species turnover. C_LIO_LIAmong the habitats, the pool showed significant phylogenetic clustering, suggesting high levels of evolutionary adaptation and strong habitat filtering. This community structure may be caused by long-term stability of the habitat and the similar requirements for co-occurring species. C_LIO_LIOur study shows the importance of different habitats on the spatial and phylogenetic structure of stonefly community assemblies and sheds light on the habitat-specific diversity that may help improve conservation practices. C_LI

evolutionary biology↗