Biology subjects

Marquis, C.

Publications and source records attributed to Marquis, C..

5 recordsLinked to original sources

bioRxiv2022

Visualization of Incrementally Learned Projection Trajectories for Longitudinal Data

Longitudinal studies that continuously generate data enable the capture of temporal variations in experimentally observed parameters, facilitating the interpretation of results in a time-aware manner. We propose IL-VIS (Incrementally Learned Visualizer), a new machine learning pipeline that incrementally learns and visualizes a progression trajectory representing the longitudinal changes in longitudinal studies. At each sampling time point in an experiment, IL-VIS generates a snapshot of the longitudinal process on the data observed thus far, a new feature that is beyond the reach of classical static models. We first verify the utility and correctness of IL-VIS using simulated data, for which the true progression trajectories are known. We find that it accurately captures and visualizes the trends and (dis)similarities between high-dimensional progression trajectories. We then apply IL-VIS to longitudinal Multi-Electrode Array data from brain cortical organoids when exposed to different levels of Quinolinic Acid, a metabolite contributing to many neuroinflammatory diseases including Alzheimers disease, and its blocking antibody. We uncover valuable insights into the organoids electrophysiological maturation and response patterns over time under these conditions.

bioinformatics↗

bioRxiv2022

Single-cell DNA methylation sequencing by combinatorial indexing and enzymatic DNA methylation conversion.

DNA methylation is a critical molecular mark involved in cellular differentiation and cell-specific processes. Single-cell whole genome DNA methylation profiling methods hold great potential to resolve the DNA methylation profiles of individual cell-types. Here we present a method that couples single-cell combinatorial indexing (sci) with enzymatic conversion (sciEM) of unmethylated cytosines. The method facilitates single-base resolution DNA methylation profiling of single-cells that is highly correlated with single-cell bisulfite-based workflows (r2 >0.99) whilst improving sequencing alignment rates, reducing adapter contamination and over-estimation of DNA methylation levels (CpG and non-CpG). As proof-of-concept we perform sciEM analysis of the temporal lobe, motor cortex, hippocampus and cerebellum of the human brain to resolve single-cell DNA methylation of all major cell-types.

genomics↗

bioRxiv2020

Strongyle-resistant sheep express their potential across environments and leave limited scope for parasite plasticity

IntroductionDrug-resistant parasites threaten livestock production. Breeding more resistant hosts could be a sustainable control strategy. Environmental variation may however alter the expression of genetic potential and directional selection toward host resistance could initiate an arms race between the host and its parasites. Methods and ResultsWe created sheep lines with high or low resistance to Haemonchus contortus. We first exposed both lines to chronic stress or to the infection by another parasite Trichostrongylus colubriformis, to test for genotype-by-environment and genotype-by-parasite species interactions respectively. Overall, between-line divergence remained significant across environmental perturbations. But we found that the impact of chronic stress on H. contortus infection varied among families and that divergence was reduced during infection by T. colubriformis. Second, we quantified genomic and transcriptomic differences in H. contortus worms collected from both lines to identify components of an arms race. We found no evidence of genetic differentiation between worms from each line. But survival to more resistant hosts was associated with enhanced expression of cuticle collagen coding genes. DiscussionBreeding for resistance hence remains a sustainable strategy that requires to anticipate the effects of environmental perturbations and to monitor worm populations.

evolutionary biology↗

bioRxiv2020

Selective vulnerability of aneuploid human cancer cells to inhibition of the spindle assembly checkpoint

Selective targeting of aneuploid cells is an attractive strategy for cancer treatment. Here, we mapped the aneuploidy landscapes of ~1,000 human cancer cell lines and classified them by their degree of aneuploidy. Next, we performed a comprehensive analysis of large-scale genetic and chemical perturbation screens, in order to compare the cellular vulnerabilities between near-diploid and highly-aneuploid cancer cells. We identified and validated an increased sensitivity of aneuploid cancer cells to genetic perturbation of core components of the spindle assembly checkpoint (SAC), which ensures the proper segregation of chromosomes during mitosis. Surprisingly, we also found highly-aneuploid cancer cells to be less sensitive to short-term exposures to multiple inhibitors of the SAC regulator TTK. To resolve this paradox and to uncover its mechanistic basis, we established isogenic systems of near-diploid cells and their aneuploid derivatives. Using both genetic and chemical inhibition of BUB1B, MAD2 and TTK, we found that the cellular response to SAC inhibition depended on the duration of the assay, as aneuploid cancer cells became increasingly more sensitive to SAC inhibition over time. The increased ability of aneuploid cells to slip from mitotic arrest and to keep dividing in the presence of SAC inhibition was coupled to aberrant spindle geometry and dynamics. This resulted in a higher prevalence of mitotic defects, such as multipolar spindles, micronuclei formation and failed cytokinesis. Therefore, although aneuploid cancer cells can overcome SAC inhibition more readily than diploid cells, the proliferation of the resultant aberrant cells is jeopardized. At the molecular level, analysis of spindle proteins identified a specific mitotic kinesin, KIF18A, whose levels were drastically reduced in aneuploid cancer cells. Aneuploid cancer cells were particularly vulnerable to KIF18A depletion, and KIF18A overexpression restored the sensitivity of aneuploid cancer cells to SAC inhibition. In summary, we identified an increased vulnerability of aneuploid cancer cells to SAC inhibition and explored its cellular and molecular underpinnings. Our results reveal a novel synthetic lethal interaction between aneuploidy and the SAC, which may have direct therapeutic relevance for the clinical application of SAC inhibitors.

cancer biology↗

bioRxiv2020

Chromosomally unstable tumor cells specifically require KIF18A for proliferation

Chromosomal instability (CIN), characterized by frequent missegregation of chromosomes during mitosis, is a hallmark of tumor cells caused by changes in the dynamics and control of microtubules that comprise the mitotic spindle1-3. Thus, CIN tumor cells may respond differently than normal diploid cells to treatments that target mitotic spindle regulation. We tested this idea by inhibiting a subset of kinesin motor proteins that control spindle microtubule dynamics and mechanics but are not required for the proliferation of near-diploid cells. Our results indicated that KIF18A was required for proliferation of CIN cells derived from triple negative breast cancer or colorectal cancer tumors but was not required in near-diploid cells. CIN tumor cells exhibited mitotic delays, multipolar spindles due to centrosome fragmentation, and increased cell death following inhibition of KIF18A. Sensitivity to KIF18A knockdown was strongly correlated with centrosome fragmentation, which required dynamic microtubules but did not depend on bipolar spindle formation or mitotic arrest. Our results indicate the altered spindle microtubule dynamics characteristic of CIN tumor cells can be exploited to reduce the proliferative capacity of CIN cells.

cell biology↗