Biology subjects

Morin, A.

Publications and source records attributed to Morin, A..

10 recordsLinked to original sources

bioRxiv2026

Evaluation of analysis modes for RNA coexpression in single-cell and bulk tissue

Coexpression of transcripts presents the most common means of computational inference of transcription factor regulation, and is often combined with other data types to infer regulatory networks. With the growing popularity of single-cell approaches, there are questions about how best to extract coexpression information from the data. Recently we reported a simulation study that explored the differences among coexpression performed at different levels: across single cells (xCell, per cell type), across subjects from pseudobulked single-cell data (xSubject, per cell type), or across subjects using bulk tissue samples (xBulk). Here we test predictions made by those models using real data. We consider both preservation (consistency of coexpression findings across different levels of analysis of the same data) and replicability across independent studies, as well as biological interpretability. We find that preservation across levels is limited, indicating the choice of analysis level will affect outcomes. We show that xCell coexpression is more replicable across studies compared to xSubject. xBulk coexpression is dominated by patterns driven by variability in cellular composition and fails to capture much coexpression that is reliably detected at finer resolutions. While all modes of analysis exhibit some enrichment for known regulatory relationships, it was highest with the xCell mode. Finally, we present a case study of the effect of analysis modes on a schizophrenia-associated pattern, reinforcing the importance of analytic choices in the interpretation and replicability of coexpression analyses. Together with our modeling study, this work emphasizes the importance of understanding sources of expression covariation as they relate to the goals of the analysis, and recommend single-cell-based data with biological replicates should be the focus of attempts to infer dynamic regulatory interactions that are more likely to be replicable by others.

bioinformatics↗

bioRxiv2025

Investigating the intraspecific diversity of Vitis vinifera responses to esca with a physiopathology approach

Woody plant dieback involves complex interactions between pathogens, plant functional traits and environmental conditions. The role of intraspecific variation in functional strategies in shaping susceptibility to dieback remains unclear, despite its importance for understanding plant adaptation to changing environments. We used a common garden containing 46 Vitis vinifera (grapevine) cultivars to test the hypothesis that differences in grapevine susceptibility to esca, a complex vascular disease leading to dieback, result from intraspecific syndromes of leaf gas exchange, wood anatomical and metabolic traits, and microbiome. Cultivars with conservative water use strategies tended to be less susceptible to esca whereas xylem anatomy did not affect esca susceptibility. Across cultivars, symptomatic plants displayed decreases in leaf gas exchange, stem starch storage and theoretical hydraulic conductivity in response to esca. Symptomatic stems accumulated more secondary metabolites (mostly glycosylated flavonoids and terpenes) in highly susceptible than in weakly susceptible genotypes, whereas stem microbial communities were unaffected. This suggests that disease expression is linked to cultivar-specific metabolic responses. Intraspecific variation in physiological strategies contributes to differences in susceptibility to a complex vascular disease. Integrative studies unravelling plant-microorganism-environment interactions are crucial to improve our understanding of complex plant diseases.

plant biology↗

bioRxiv2024

The assessment of therapeutic autophagy inhibition in NF1 mutated tumor cells

MAPK pathway activation is found across central nervous system tumors. Neurofibromin 1 (NF1) protein is a GTPase-activating protein and tumor suppressor that negatively regulates RAS protein activity. A NF1 loss of function mutation results in MAPK pathway upregulation and is associated with pediatric gliomas. We previously demonstrated autophagy inhibition improves tumor response to BRAF inhibition. Here we investigate the role of autophagy in NF1 cells in the presence or absence of MEK inhibition (MEKi). NF1 wild type (WT) and NF1 knockout (KO) (HSC1{lambda}, immortalized human Schwann) cells were evaluated. NF1 loss was confirmed, and cell growth was monitored by Incucyte. MAPK/ERK pathway upregulation and autophagy were evaluated via Western blot analysis and RAS pull-down. Effects of MEKi, autophagy inhibition (pharmacologic and genetic), and combination therapy were evaluated via short- and long-term growth assays. NF1 KO cells exhibited MAPK pathway upregulation and increased growth. Additionally, NF KO cells demonstrated increased autophagic activity. Loss of NF1 resulted in increased sensitivity to MEKi and autophagy inhibition alone and in combination. We also demonstrate that the autophagy inhibitor chloroquine (CQ) can improve MEKi sensitivity in a patient harboring a somatic mutation of NF1. This combination is currently being evaluated in clinical trial (NCT04201457).

cancer biology↗

bioRxiv2024

Joint operation of the CO2 concentrating mechanism and photorespiration in green algae during acclimation to limiting CO2

Due to low availability of CO2 in aquatic environment, microalgae have evolved a CO2 concentrating mechanism (CCM). It has long been thought that operation of CCM would suppress photorespiration by increasing the CO2 concentration at the Rubisco active site, but experimental evidence is scarce. To better explore the function of photorespiration in algae, we first characterized a Chlamydomonas reinhardtii mutant defected in low-CO2 inducible 20 (LCI20) and show that LCI20 is a chloroplast-envelope glutamate/malate transporter playing a role in photorespiration. By monitoring growth and glycolate excretion in mutants deficient in either CCM or photorespiration, we conclude that: i. CCM induction does not depend on photorespiration, ii. glycolate excretion protects algal cells from the toxicity of unmetabolized photorespiratory intermediates, iii. photorespiration is active at low CO2 when the CCM is operational. This work provides a foundation for a better understanding of the carbon cycle in the ocean where significant glycolate concentrations have been found.

plant biology↗

bioRxiv2024

Identifying Reproducible Transcription Regulator Coexpression Patterns with Single Cell Transcriptomics

The proliferation of single cell transcriptomics has potentiated our ability to unveil patterns that reflect dynamic cellular processes such as the regulation of gene transcription. In this study, we leverage a broad collection of single cell RNA-seq data to identify the gene partners whose expression is most coordinated with each human and mouse transcription regulator (TR). We assembled 120 human and 103 mouse scRNA-seq datasets from the literature (>28 million cells), constructing a single cell coexpression network for each. We aimed to understand the consistency of TR coexpression profiles across a broad sampling of biological contexts, rather than examine the preservation of context-specific signals. Our workflow therefore explicitly prioritizes the patterns that are most reproducible across cell types. Towards this goal, we characterize the similarity of each TRs coexpression within and across species. We create single cell coexpression rankings for each TR, demonstrating that this aggregated information recovers literature curated targets on par with ChIP-seq data. We then combine the coexpression and ChIP-seq information to identify candidate regulatory interactions supported across methods and species. Finally, we highlight interactions for the important neural TR ASCL1 to demonstrate how our compiled information can be adopted for community use. Author SummaryA common way to analyze gene expression (transcriptomics) data is to correlate gene transcript levels across samples for every pair of genes (coexpression). Coordinated expression between genes may imply a shared biological function, though this warrants cautious interpretation given assumptions about cellular processes inferred from RNA abundances alone. Still, coexpression inference is often used to nominate genes whose expression may be controlled by transcription regulators (TRs). The rapid generation of diverse single cell transcriptomics data has unlocked our ability to discover coexpression patterns across individual cells -- though these signals are often noisy. Reproducible patterns across studies can help distinguish meaningful biological relationships from spurious correlations. We used this study to analyze a broad collection of single cell data spanning numerous tissues in human and mouse to infer global TR coexpression patterns. We aimed to learn which interactions were generally observable, to better potentiate future examinations of reproducible coexpression in specific contexts. We evaluate the predictive performance of these global single cell coexpression rankings using independent gene regulation evidence, and highlight TR-gene pairs that are supported across data modalities as well as species. By disseminating these rankings, we hope that other researchers can extract insight for their own TRs of interest.

bioinformatics↗

bioRxiv2023

Mutant mice lacking alternatively spliced p53 isoforms unveil Ackr4 as a male-specific prognostic factor in Myc-driven B-cell lymphomas

The Trp53 gene encodes several isoforms of elusive biological significance. Here we show that mice lacking the Trp53 Alternatively Spliced (AS) exon, thereby expressing the canonical p53 protein but not isoforms with the AS C-terminus, have unexpectedly lost a male-specific protection against Myc-induced B-cell lymphomas. Lymphomagenesis was delayed in p53+/+ E-Myc males compared to p53{Delta}AS/{Delta}AS E-Myc males, but also compared to p53+/+ E-Myc and p53{Delta}AS/{Delta}AS E-Myc females. Pre-tumoral splenic cells from p53+/+ E-Myc males exhibited a higher expression of Ackr4, encoding an atypical chemokine receptor with tumor suppressive effects. We identified Ackr4 as a p53 target gene whose p53-mediated transactivation is inhibited by estrogens, and as a male-specific factor of good prognosis relevant for murine E-Myc-induced and human Burkitt lymphomas. Furthermore, the knockout of ACKR4 increased the chemokine-guided migration of Burkitt lymphoma cells. These data demonstrate the functional relevance of alternatively spliced p53 isoforms and reveal sex disparities in Myc-driven lymphomagenesis.

cancer biology↗

bioRxiv2022

Inactivated SARS-CoV-2 Reprograms the Tumor Immune Microenvironment and Improves Murine Cancer Outcomes

Following the breakthrough of immune check point inhibitors (ICIs), a new era of immuno-oncology agents has emerged and established immunotherapy as a part of cancer treatment. Despite the improving outcomes of ICIs, many patients with initial response are known to develop acquired resistance later. There is increasing interest in utilizing other stimulatory means, such as anti-pathogen immune responses to induce anti-tumor immune responses. The immunostimulatory effects of anti-pathogen-treated tumors in combinations with ICI are known to potentially amplify anti-tumor immunity resulting in increased tumor responses and improved outcomes. Anti-pathogen-treated tumors can become immune-infiltrated "hot" tumors and demonstrate higher treatment response rates and improved survival. Our research group has previously demonstrated that tumors can be converted from "cold" to "hot" by intratumoral injection of a commercially available seasonal influenza vaccine. In continuation with our work, in deciphering the role of anti-viral immunity in the context of tumor immunology, we studied the role of inactivated SARS-CoV-2 virus as anti-tumor agent. Here we report that intratumoral injections of inactivated SARS-CoV-2 convert the immunologically cold tumors to hot by generating anti-tumor-mediated CD8+ T cells. Our findings suggest that inactivated SARS-CoV-2 can be used as an immune modulator in immunotherapy for melanoma and triple-negative breast cancer.

cancer biology↗

bioRxiv2021

The Effect of COVID-19 on the Postdoctoral Experience: a comparison of pre-pandemic and pandemic surveys.

In the interest of advocating for the postdoctoral community in the United States, we present results from survey data collected before and during the COVID-19 pandemic on the same population of postdocs. In 2019, 5,929 postdocs in the US completed a comprehensive survey, and in 2020, a subset completed a follow-up survey several months into the pandemic. The results show that the pandemic has substantially impacted postdocs mental health and wellness irrespective of gender, race, citizenship, or other identities. Postdocs also reported a significant impact on their career trajectories and progression, reduced confidence in achieving career goals, and negative perceptions of the job market compared to pre-COVID-19. International postdocs also reported experiencing distinct stressors due to the changes in immigration policy. Notably, having access to Postdoctoral Associations and Postdoctoral Offices positively impacted postdocs overall well-being and helped mitigate the personal and professional stresses and career uncertainties caused by the pandemic. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/468693v2_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@174d7e3org.highwire.dtl.DTLVardef@9893dorg.highwire.dtl.DTLVardef@114470org.highwire.dtl.DTLVardef@1a4278f_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract of survey responses to: Why or how has your research been disrupted or not disrupted due to the pandemic? Overall, postdocs responded with feelings of loss of control as the pandemic was acting upon them and taking away their ability to complete their work. C_FIG

scientific communication and education↗

bioRxiv2021

Experiment level curation identifies high confidence transcriptional regulatory interactions in neurodevelopment

To facilitate the development of large-scale transcriptional regulatory networks (TRNs) that may enable in-silico analyses of disease mechanisms, a reliable catalogue of experimentally verified direct transcriptional regulatory interactions (DTRIs) is needed for training and validation. There has been a long history of using low-throughput experiments to validate single DTRIs. Therefore, we hypothesize that a reliable set of DTRIs could be produced by curating the published literature for such evidence. In our survey of previous curation efforts, we identified the lack of details about the quantity and the types of experimental evidence to be a major gap, despite the importance of such details for the identification of bona fide DTRIs. We developed a curation protocol to inspect the published literature for support of DTRIs at the experiment level, focusing on genes important to the development of the mammalian nervous system. We sought to record three types of low-throughput experiments: Transcription factor (TF) perturbation, TF-DNA binding, and TF-reporter assays. Using this protocol, we examined a total of 1,310 papers to assemble a collection of 1,499 unique DTRIs, involving 251 TFs and 825 target genes, many of which were not reported in any other DTRI resource. The majority of DTRIs (965, 64%) were supported by two or more types of experimental evidence and 27% were supported by all three. Of the DTRIs with all three types of evidence, 170 had been tested using primary tissues or cells and 44 had been tested directly in the central nervous system. We used our resource to document research biases among reports towards a small number of well-studied TFs. To demonstrate a use case for this resource, we compared our curation to a previously published high-throughput perturbation screen and found significant enrichment of the curated targets among genes differentially expressed in the developing brain in response to Pax6 deletion. This study demonstrates a proof-of-concept for the assembly of a high confidence DTRI resource in order to support the development of large-scale TRNs. Author SummaryThe capacity to computationally reconstruct gene regulatory networks using large-scale biological data is currently limited by the absence of a high confidence set of one-to-one regulatory interactions. Given the lengthy history of using small scale experimental assays to investigate individual interactions, we hypothesize that a reliable collection of gene regulatory interactions could be compiled by systematically inspecting the published literature. To this end, we developed a curation protocol to examine and record evidence of regulatory interactions at the individual experiment level. Focusing on the area of brain development, we applied our pipeline to 1,310 publications. We identified 3,601 individual experiments, providing detailed information about 1,499 regulatory interactions. Many of these interactions have verified activity specifically in the embryonic brain. By capturing reports of regulatory interactions at this level of granularity, we present a resource that is more interpretable than other similar resources.

genomics↗

bioRxiv2019

GSDMA drives the most replicated association with asthma in naïve CD4+ T cells

BackgroundThe 17q12-21 locus is the most replicated association with asthma. However, no study had described the genetic mechanisms underlying this association considering all genes of the locus in immune cell samples isolated from asthmatic and non-asthmatic individuals.\n\nObjectiveThis study takes benefit of samples from naive CD4+ T cells and eosinophils isolated from the same 200 individuals to describe specific interactions between genetic variants, gene expression and DNA methylation levels for the 17q12-21 asthma locus.\n\nMethods and ResultsAfter isolation of naive CD4+ T cells and eosinophils from blood samples, next generation sequencing was used to measure DNA methylation levels and gene expression counts. Genetic interactions were then evaluated considering genetic variants from imputed genotype data. In naive CD4+ T cells but not eosinophils, 20 SNPs in the fourth and fifth haplotype blocks modulated both GSDMA expression and methylation levels, showing an opposite pattern of allele frequencies and expression counts in asthmatics compared to controls. Moreover, negative correlations have been measured between methylation levels of CpG sites located within the 1.5 kb region from the transcription start site of GSDMA and its expression counts.\n\nConclusionAvailability of sequencing data from two key cell types isolated from asthmatic and non-asthmatic individuals allowed identifying a new gene in naive CD4+ T cells that drives the association with the 17q12-21 locus, leading to a better understanding of the genetic mechanisms taking place in it.

genetics↗