Biology subjects

Mekonen, H.

Publications and source records attributed to Mekonen, H..

5 recordsLinked to original sources

bioRxiv2025

Commensal taxa in gut microbiota limit antibiotic resistance during extended oral antibiotic use

Certain bacterial infections, such as those involving prosthetics, can require antimicrobial therapy over months to years, potentially increasing the burden of antimicrobial resistance. Here we longitudinally track the antimicrobial resistome in mice during continuous antibiotic dosing over 21 months. The burden of antibiotic resistance genes (ARGs) initially increases, but, surprisingly, declines in later months, approaching levels observed in untreated animals. ARG burden is regulated by taxonomy and declines as ARG-harboring taxa that initially bloom are replaced by commensals. Furthermore, we find that the dynamics of antibiotic-induced ARG burden are influenced by age-related differences in microbial taxonomy and can be removed by fecal microbiota transplantation. We show that commensals may regulate the resistome by limiting the growth of ARG-harboring taxa, thereby providing antimicrobial expansion resistance.

microbiology↗

bioRxiv2024

Zebrahub-Multiome: Uncovering Gene Regulatory Network Dynamics During Zebrafish Embryogenesis

During embryonic development, gene regulatory networks (GRNs) drive molecular differentiation of cell types. However, the temporal dynamics of these networks remain poorly understood. Here, we present Zebrahub-Multiome, a single-cell multiomic atlas that captures chromatin accessibility and gene expression from 94,562 cells across six stages of zebrafish embryogenesis (10-24 hours post-fertilization), capturing key developmental stages from the end of gastrulation to the onset of organogenesis. By measuring regulatory element activity alongside transcriptional output from the same cells, we identify 640,000 cis-regulatory elements organized into 402 hierarchically structured modules corresponding to specific developmental pathways. Early embryonic stages employ broadly shared regulatory programs that progressively fragment into lineage-specific modules. Timeresolved gene regulatory network inference reveals that transcription factors undergo functional transitions - from multilineage regulators to specialized, lineage-committed factors. These quantitative measurements reveal the regulatory network rewiring that drives cell fate specification. Our interactive web portal (zebrahub.org/epigenomics) enables exploration of gene dynamics, regulatory networks, and perturbation predictions, providing a quantitative framework for understanding vertebrate developmental regulation.

developmental biology↗

bioRxiv2023

Single-nucleus RNA sequencing provides insights into the GL261-GSC syngeneic mouse model of glioblastoma

Glioblastoma (GBM) is an aggressive tumor with very bad prognosis. The urgent need to find new effective therapies is challenged by the unique characteristics of GBM, including high intra and intertumoral heterogeneity. Using single-nucleus transcriptomics (snRNA-seq), we characterized the panorama of a preclinical immunocompetent murine model based in the implantation of mouse glioblastoma stem cells (GL261-GSCs) into the brain parenchyma. Additionally, we performed Visium spatial transcriptomics in the in vivo model to confirm the location of annotated cells. To understand the technical bias of this approach, we performed two scRNA-seq methods in GBM cells. We thoroughly characterized the tumor microenvironment (TME) at early and late stages of tumor development and upon treatment with temozolomide (TMZ), the standard of care for patients with GBM, and with Tat-Cx43266-283, a promising experimental treatment. We identified prominent GBM targets that can be addressed using this preclinical model, such as Grik2, Nlgn3, Gap43 or Kcnn4, which are involved in electrical and synaptic integration of GBM cells into neural circuits, as well as the expression of Nt5e, Cd274 or Irf8, which indicates the development of immune evasive properties in these GBM cells. In agreement, snRNA-seq unveiled high expression of several immunosuppressive-associated molecules in immune cells, such as Csf1r, Arg1, Mrc1 and Tgfb1, suggesting the development of an immunosuppressive microenvironment. We also show the landscape of cytokines, cytokine receptors, checkpoint ligands and receptors in tumor and TME cells, which are crucial data for a rational design of immunotherapy studies. Thus, Mrc1, PD-L1, TIM-3 or B7-H3 are among the immunotherapy targets that can be addressed in this model. Finally, the comparison of the preclinical GL261-GSC GBM model with human GBM subtypes unveiled important similarities with the recently identified TMEmed human GBM, indicating that preclinical data obtained in GL261-GSC GBM model might be applied to TMEmed human GBM, improving patient stratification in clinical trials. In conclusion, this work provides crucial information for future preclinical studies in GBM improving their clinical application.

neuroscience↗

bioRxiv2023

R2C2+UMI: Combining concatemeric consensus sequencing with unique molecular identifiers enables ultra-accurate sequencing of amplicons on Oxford Nanopore Technologies sequencers

The sequencing of PCR amplicons is a core application of high-throughput sequencing technology. Using unique molecular identifiers (UMIs), individual amplified molecules can be sequenced to very high accuracy on an Illumina sequencer. However, Illumina sequencers have limited read length and are therefore restricted to sequencing amplicons shorter than 600bp unless using inefficient synthetic long-read approaches. Native long-read sequencers from Pacific Biosciences and Oxford Nanopore Technologies can, using consensus read approaches, match or exceed Illumina quality while achieving much longer read lengths. Using a circularization-based concatemeric consensus sequencing approach (R2C2) paired with UMIs (R2C2+UMI) we show that we can sequence [~]550nt antibody heavy-chain (IGH) and [~]1500nt 16S amplicons at accuracies up to and exceeding Q50 (<1 error in 100,0000 sequenced bases), which exceeds accuracies of UMI-supported Illumina paired sequencing as well as synthetic long-read approaches.

genomics↗

bioRxiv2023

Zebrahub - Multimodal Zebrafish Developmental Atlas Reveals the State Transition Dynamics of Late Vertebrate Pluripotent Axial Progenitors

Elucidating the developmental processes of organisms requires a comprehensive understanding of cellular lineages in the spatial, temporal, and molecular domains. In this study, we introduce Zebrahub, a dynamic atlas of zebrafish embryonic development that integrates single-cell sequencing time course data with lineage reconstructions facilitated by light-sheet microscopy. This atlas offers high-resolution and in-depth molecular insights into zebrafish development, achieved through the sequencing of individual embryos across ten developmental stages, complemented by trajectory reconstructions. Zebrahub also incorporates an interactive tool to navigate the complex cellular flows and lineages derived from light-sheet microscopy data, enabling in silico fate mapping experiments. To demonstrate the versatility of our multi-modal resource, we utilize Zebrahub to provide fresh insights into the pluripotency of Neuro-Mesodermal Progenitors (NMPs). Our publicly accessible web-based platform, Zebrahub, is a foundational resource for studying developmental processes at both transcriptional and spatiotemporal levels, providing researchers with an integrated approach to exploring and analyzing the complexities of cellular lineages during zebrafish embryogenesis.

developmental biology↗