Biology subjects

Popov, D.

Publications and source records attributed to Popov, D..

5 recordsLinked to original sources

bioRxiv2026

A Joint Promoterome-Proteome Atlas Highlights the Molecular Diversity of Human Skeletal Muscles

More than 600 distinct skeletal muscles constitute up to 40% of the total mass of the human body. Human skeletal muscles differ in anatomical position, morphology, origin, and function, but the diversity of their molecular phenotypes, the gene expression and protein abundance profiles, remains poorly explored. Here, we report the large-scale CAGE-Seq promoterome profiling of 75 human skeletal muscles, complemented by 22 matched proteomes obtained with mass spectrometry. We identified 37001 transcribed regulatory elements and 1804 protein groups encompassing 1895 proteins, 80% of which demonstrated non-uniform expression across different muscles. The skeletal muscles of the eye, tongue, and diaphragm had the most distinctive molecular phenotypes, while the overall diversity was driven by hundreds of transcription factors with tissue-specific activity. By analyzing the allelic imbalance of CAGE-Seq reads, we discovered 6653 allele-specific single-nucleotide variants often coinciding with muscle-related GWAS SNPs, including muscle volume. Finally, we provide an interactive online atlas of transcriptomic and proteomic molecular phenotypes, facilitating further studies of gene regulation and heritable pathologies of skeletal muscles.

genomics↗

bioRxiv2026

A Multispecies, Modality-Agnostic Scalable In Vivo Mosaic Screening Platform for Therapeutic Target Discovery

Validating therapeutic targets for complex diseases requires investigating gene functions within native tissue architectures rather than reductionist in vitro models. Here we present a modality-agnostic AAV-based in vivo high-throughput screening platform capable of delivering knockouts, gain-of-function, and synthetic miRNA knockdowns directly to cells within the diseased environment. This system scales to hundreds of perturbations and is adaptable to diverse species and organ systems. To translate high-dimensional screen data into therapeutic assessment, we established a curated analysis framework that scores single-cell transcriptomes against human disease-specific molecular signatures. This method enables quantitative ranking of targets across distinct biological domains ranging from structural fibrosis to inflammatory signaling, to narrow in on the therapeutic potential of each intervention. We applied this strategy to screen loss- and gain-of-function libraries in a murine pulmonary fibrosis model and within the spontaneously osteoarthritic joints of aged horses, identifying metabolic, antifibrotic, and immunomodulatory targets. Importantly, our analysis framework successfully predicted functional outcomes in orthogonal human ex vivo tissue models, including soluble collagen reduction in lung slices and glycosaminoglycan restoration in cartilage, thus establishing a powerful paradigm for prioritizing therapeutic targets by uniting human disease signatures with highly multiplexed in vivo functional genomics.

systems biology↗

bioRxiv2025

Wilms tumor 1 impairs apoptotic clearance of fibroblasts in distal fibrotic lung lesions

Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease characterized by impaired fibroblast clearance and excessive extracellular matrix (ECM) protein production. Wilms Tumor 1 (WT1), a transcription factor, is selectively upregulated in IPF fibroblasts. However, the mechanisms by which WT1 contributes to fibroblast accumulation and ECM production remain unknown. Here, we investigated the heterogeneity of WT1-expressing mesenchymal cells using single-nucleus RNA sequencing of distal lung tissues from IPF patients and control donors. WT1 was selectively upregulated in a subset of IPF fibroblasts that co-expressed several pro- survival and ECM genes. The results of both loss-of-function and gain-of-function studies are consistent with a role for WT1 as a positive regulator of pro-survival genes to impair apoptotic clearance and promote ECM production. Fibroblast-specific overexpression of WT1 augmented fibroproliferation, myofibroblast accumulation, and ECM production during bleomycin-induced pulmonary fibrosis in young and aged mice. Together, these findings suggest that targeting WT1 is a promising strategy for attenuating fibroblast expansion and ECM production during fibrogenesis.

pathology↗

bioRxiv2025

Ferret model of bleomycin-induced lung injury shares features of human idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease with limited therapeutic options. The development of effective therapies has been hindered by the lack of models that recapitulate key features of human disease. Here we report a bleomycin-induced ferret PF model characterized by an irreversible decrease in pulmonary compliance and an increase of opacification, accompanied by "honeycomb cyst-like" structures and "proximalization" of distal lung epithelium. Cellular and molecular analysis by single-nucleus RNA sequencing revealed a significant shift in distal lung epithelium towards proximal epithelial phenotype. Importantly, a histopathological pattern of bronchiolization encompassing divergent atypical epithelial cells and KRT17+/TP63+/KRT5low "basaloid-like" cells was present in the distal fibrotic lung lesions. Trajectory analysis revealed AT2 cells transition through multiple cell-states in bleomycin injured ferret lungs, particularly AT2 to KRT8high/KRT7low/SOX4+ and eventually to KRT8high/KRT7high/SFN+/TP63+/KRT5low "basaloid-like" cells. Further, immunofluorescence analyses demonstrated KRT7 and KRT8 populations reside overlaying the ACTA2-positive myofibroblasts in fibrotic foci, implying their pro-fibrogenic activity similar to human IPF lungs. Collectively, our results provide evidence that bleomycin-induced lung injury in ferrets recapitulates pathophysiological, cellular, and molecular features of human IPF, suggesting that they may be a reliable model for understanding mechanisms of IPF pathogenesis and for testing therapeutic strategies for treatment of IPF. Take Home MessageBleomycin-induced acute lung injury in the ferret recapitulates pathophysiological, cellular, and molecular features of human IPF; thus the ferret may be a reliable species for studying mechanisms of IPF pathogenesis and testing therapeutic strategies.

pathology↗

bioRxiv2025

The 16p11.2 microdeletion influences how early-life microbiota perturbations affect hippocampal development and behavior throughout the lifespan

Neurodevelopmental disorders (NDDs) arise from interactions between genetic factors and environmental exposures, with infancy representing a critical period of vulnerability. This exploratory, preclinical study investigated whether the 16p11.2 microdeletion (16pDel), a NDD-associated genetic variant, exacerbates the effects of early-life therapeutic antibiotic exposure on the gut microbiome, hippocampal development, and behavior. Cefdinir, selected for its epidemiological association with NDD risk, acutely perturbed the gut microbiome, causing sustained reductions in Lachnospiraceae. These changes were followed by alterations in sociability, risk assessment, and associative learning. Notably, only cefdinir-exposed 16pDel mice exhibited altered hippocampal stem cell dynamics and gene expression, demonstrating genotype-dependent susceptibility. Increased intestinal permeability and alterations in arginine biosynthesis and glycerophospholipid metabolism implicate gut barrier dysfunction as a contributing factor. Our findings suggest that genetic composition can exacerbate neurodevelopmental consequences of early-life microbiome perturbations, identify metabolic pathways for potential interventions, and support cautious antibiotic use during infancy, especially in genetically vulnerable populations.

neuroscience↗