Biology subjects

Meyer, I.

Publications and source records attributed to Meyer, I..

7 recordsLinked to original sources

bioRxiv2026

Characterization and pharmacological modulation of Alzheimers disease-associated human microglial states

Microglia are central mediators of Alzheimers disease (AD) pathogenesis, yet the mechanisms driving disease-associated microglial states and their therapeutic modulation remain poorly understood. Here, we integrated single-nucleus transcriptomic datasets across the AD spectrum and identified disease- and lipid-associated microglia (DLaM) as a major AD-enriched population linked to genetic risk, neuropathology and cognitive decline. To model this state experimentally, we screened AD-relevant perturbations in human induced pluripotent stem cell (hiPSC)-derived microglia and found that ferric ammonium citrate (FAC) reproducibly induced a DLaM-like state characterized by lipid accumulation, lysosomal dysfunction and impaired A{beta} phagocytosis. Using a transcriptomics-based state-reversion screen, we identified LY2090314 as a potent modulator that restored microglial function and induced a distinct lysosomal-metabolic state. These findings establish a framework for transcriptomic disease-state-guided therapeutic discovery in AD.

neuroscience↗

bioRxiv2025

T6SS4 is heterogeneously expressed in Y. pseudotuberculosis and is a target for transcriptional and post-transcriptional regulation

The type VI secretion system (T6SS) is a complex secretion system encoded by many Gram-negative bacteria to translocate effector proteins directly into target cells. Due to its high complexity and energy-intensive firing process, regulation of the T6SS is tightly controlled in many organisms. Y. pseudotuberculosis encodes four complete T6SS clusters but lacks genes implicated in T6SS gene regulation in other microorganisms, indicating a distinct control mechanism. Here, we could show that the T6SS4 of Y. pseudotuberculosis is heterogeneously expressed within a population, which is determined by the transcriptional T6SS4 activator RovC. Moreover, the T6SS4 and RovC are embedded in a complex and global regulatory network, including the global post-transcriptional regulator CsrA, the Yersinia modulator A (YmoA), the global protease Lon, and RNases (PNP and RNase III). Post-transcriptional processing of the T6SS4 polycistron and different transcript stability within the operon also achieve a higher regulatory complexity. In summary, our work provides new insights into the sophisticated and complex regulatory network of the T6SS4 of Y. pseudotuberculosis, which clearly differs from regulation in other organisms. Authors summaryBacteria use a specialized multi-protein complex called the Type VI secretion system (T6SS) to inject toxic proteins into other cells to compete with target microorganisms or to infect host organisms. While the T6SS has been extensively studied in some model organisms, much less is known about the function and regulation of the four T6SS clusters of the food-borne human pathogen Yersinia pseudotuberculosis. In this study, we found that the T6SS4 of Y. pseudotuberculosis is only expressed in a small subpopulation in vitro. This suggests that its regulation is fundamentally different from what is known in other organisms. We show that a complex regulatory network regulates T6SS4 gene expression, and the T6SS4 transcript is post-transcriptionally processed, resulting in different mRNA levels of the individual T6SS components. These findings contribute to a deeper understanding of how bacteria, especially Y. pseudotuberculosis, regulate complex secretion systems at multiple levels.

microbiology↗

bioRxiv2024

Tabula Glycine: The whole-soybean single-cell resolution transcriptome atlas

Soybean (Glycine max) is an essential source of protein and oil with high nutritional value for human and animal consumption. To enhance our understanding of soybean biology, it is essential to have accurate information regarding the expression of each of its 55,897 protein-coding genes. Here, we present "Tabula Glycine", the soybean single-cell resolution transcriptome atlas. This atlas is composed of single-nucleus RNA-sequencing data of nearly 120,000 nuclei isolated from 10 different Glycine max organs and morphological structures comprising the entire soybean plant. These nuclei are grouped into 157 different clusters based on their transcriptomic profiles. Among genes, the pattern of activity of transcription factor genes is sufficient to define most cell types and their organ/morphological structure of origin, suggesting that transcription factors are key determinants of cell identity and function. This unprecedented level of resolution makes the Tabula Glycine a unique resource for the plant and soybean communities.

plant biology↗

bioRxiv2024

RNase-mediated reprogramming of Yersinia virulence

RNA degradation is an essential process that allows bacteria to regulate gene expression and has emerged as an important mechanism for controlling virulence. However, the individual contributions of RNases in this process are mostly unknown. Here, we report that of 11 tested potential RNases of the intestinal pathogen Yersinia pseudotuberculosis, two, the endoribonuclease RNase III and the exoribonuclease PNPase, repress the synthesis of the master virulence regulator LcrF. LcrF activates the expression of virulence plasmid genes encoding the type III secretion system (Ysc-T3SS) and its substrates (Yop proteins), that are employed to inhibit immune cell functions during infection. Loss of both RNases led to an increase in lcrF mRNA levels and stability. Our work indicates that PNPase exerts its influence via YopD, known to accelerate lcrF mRNA degradation. Loss of RNase III results in the downregulation of the CsrB and CsrC RNAs, leading to increased availability of active CsrA, which has previously been shown to enhance lcrF mRNA translation and stability. Other factors that influence the translation process and were found to be differentially expressed in the RNase III-deficient mutant could support this process. Transcriptomic profiling further revealed that Ysc-T3SS-mediated Yop secretion leads to global reprogramming of the Yersinia transcriptome with a massive shift of the expression from chromosomal towards virulence plasmid-encoded genes. A similar extensive transcriptional reprogramming was also observed in the RNase III-deficient mutant under non-secretion conditions. This illustrates that RNase III enables immediate coordination of virulence traits, such as Ysc-T3SS/Yops, with other functions required for host-pathogen interactions and survival in the host. Author SummaryBacterial pathogens need to quickly adapt the expression of virulence- and fitness-relevant traits in response to host defenses. Pathogenic Yersinia species rapidly upregulate a type III secretion system (T3SS) to inject antiphagocytic and cell toxic effector proteins, named Yersinia outer proteins (Yops), into attacking immune cells. For this purpose, they display complex and resilient regulatory mechanisms. At the post-transcriptional level, this is mediated by different RNA-binding regulators including YopD and CsrA, while the fate of mRNAs is balanced by ribonucleases. Here, we demonstrate that out of 11 tested putative RNases of Yersinia, two major RNases, the endoribonuclease RNase III, and the exonuclease and degradosome component PNPase play a crucial role in the activation of the Ysc-T3SS/Yop machinery. We show that they promote the decay of the lcrF mRNA encoding the common transcriptional activator LcrF of the Ysc-T3SS/Yop components. PNPase seems to act through the control of the effector YopD, known to promote the decay of the lcrF transcript. In contrast, RNase III triggers processes that reduce lcrF mRNA translation and stability, and involve CsrA. A transcriptome analysis further revealed that RNase III controls a series of events that include rapid and massive genetic reprogramming from mainly chromosomal-encoded genes to virulence-plasmid-encoded ysc-T3SS/yop genes. This control process does not only ensure immediate counter-measures during an immune attack, it also helps to overcome accompanying energetic and stress burdens and allows to rapidly readjust the genetic program after a successful defense.

microbiology↗

bioRxiv2021

Species coexistence and temporal environmental fluctuations: a quantitative comparison between stochastic and seasonal variations.

Temporal environmental variations may promote diversity in communities of competing populations. Here we compare the effect of environmental stochasticity with the effect of periodic (e.g., seasonal) cycles, using analytic solutions and individual-based Monte-Carlo simulations. Even when stochasticity facilitates coexistence it still allows for rare sequences of bad years that may drive a population to extinction, therefore the stabilizing effect of periodic variations is stronger. Correspondingly, the mean time to extinction grows exponentially with community size in periodic environment and switch to power-law dependence under stochastic fluctuations. On the other hand, the number of temporal niches in periodic environment is typically lower, so as diversity increases stochastic temporal variations may support higher species richness.

ecology↗

bioRxiv2019

Widespread FUS mislocalization is a molecular hallmark of ALS

Amyotrophic lateral sclerosis (ALS)-causing mutations clearly implicate ubiquitously expressed and predominantly nuclear RNA binding proteins (RBPs), which form pathological cytoplasmic inclusions in this context. However, the possibility that wild-type RBPs mislocalize without necessarily becoming constituents of ALS cytoplasmic inclusions themselves remains unexplored. We hypothesized that nuclear-to-cytoplasmic mislocalization of the RBP Fused in Sarcoma (FUS), in an unaggregated state, may occur more widely in ALS that previously recognized. To address this hypothesis, we analysed motor neurons (MNs) from an human ALS induced-pluripotent stem cells (iPSC) model caused by the VCP mutation. Additionally, we examined mouse transgenic models and post-mortem tissue from human sporadic ALS cases. We report nuclear-to-cytoplasmic mislocalization of FUS in both VCP-mutation related ALS and, crucially, in sporadic ALS spinal cord tissue from multiple cases. Furthermore, we provide evidence that FUS protein binds to an aberrantly retained intron within the SFPQ transcript, which is exported from the nucleus into the cytoplasm. Collectively, these data support a model for ALS pathogenesis whereby aberrant intron-retention in SFPQ transcripts contributes to FUS mislocalization through their direct interaction and nuclear export. In summary, we report widespread mislocalization of the FUS protein in ALS and propose a putative underlying mechanism for this process.

neuroscience↗

bioRxiv2018

A gene expression atlas of embryonic neurogenesis in Drosophila reveals complex spatiotemporal regulation of lncRNAs.

Cell type specification during early nervous system development in Drosophila melanogaster requires precise regulation of gene expression in time and space. Resolving the programs driving neurogenesis has been a major challenge owing to the complexity and rapidity with which distinct cell populations arise. To resolve the cell type-specific gene expression dynamics in early nervous system development, we have sequenced the transcriptomes of purified neurogenic cell types across consecutive time points covering critical events in neurogenesis. The resulting gene expression atlas comprises a detailed resource of global transcriptome dynamics that permits systematic analysis of how cells in the nervous system acquire distinct fates. We resolve known gene expression dynamics and uncover novel expression signatures for hundreds of genes among diverse neurogenic cell types, most of which remain unstudied. We also identified a set of conserved and processed long-noncoding RNAs (lncRNAs) that exhibit spatiotemporal expression during neurogenesis with exquisite specificity. LncRNA expression is highly dynamic and demarcates specific subpopulations within neurogenic cell types. Our spatiotemporal transcriptome atlas provides a comprehensive resource to investigate the function of coding genes and noncoding RNAs during critical stages of early neurogenesis.\n\nSummary statementWe present a spatiotemporal transcriptome during early Drosophila embryonic nervous system development, revealing a complex cell type-specific network of mRNAs and IncRNAs.

developmental biology↗