Biology subjects

Jean, P.

Publications and source records attributed to Jean, P..

4 recordsLinked to original sources

bioRxiv2026

Genetic demultiplexing and transcript start site identification from nanopore sequencing of 10x Genomics multiome libraries

Short-read Illumina sequencing of 10x Genomics single-nucleus multiome libraries captures only the 3 end of RNA transcripts, losing transcription start site (TSS) information. Here we demonstrate nanopore sequencing of 10x multiome libraries, which enables the profiling of full length transcripts. We show concordance with common short-read sequencing based workflows including successful genetic demultiplexing of nanopore data despite its higher error rate. We compare TSS identified using nanopore sequencing of multiome cDNA to those identified using a short-read 5 assay, and provide an optimized approach for the preprocessing of nanopore reads prior to TSS identification. We find that nanopore sequencing of multiome cDNA captures a median of 63% of the TSS detected by the 5 assay.

bioinformatics↗

bioRxiv2026

Phenotypic reversion and target prioritization for cellular inflammation via representation learning with foundation models

The identification of genetic perturbations that can reverse disease-associated cellular phenotypes toward a healthy state is a central challenge in early drug discovery. We present a proof-of-concept framework leveraging single-cell foundation models (scFMs) and a large-scale Perturb-seq dataset to prioritize targets for phenotypic reversion of cellular inflammation. We incorporated both basal and proinflammatory signaling conditions, specifically stimulation with interleukin-1 beta (IL-1{beta}) and tumor necrosis factor alpha (TNF-), to assess whether atherosclerotic disease-relevant stimulation improved identification of genes and pathways critical to disease progression. Our dataset comprised 864,115 endothelial cells subjected to 1,740 unique genetic perturbations. Through having both conditions, we identified targets that exhibited differential effects on gene expression dependent on cellular state. Using scFMs, we embedded single-cell transcriptomes into high-dimensional latent spaces and ranked perturbations by their ability to shift the inflammatory transcriptomic profile toward that of untreated controls. Benchmarking against both annotated gene sets and expert-curated targets, we found robust enrichment for known regulators of inflammation and biologically relevant targets, despite these models having no prior information about these targets. Importantly, including both basal and proinflammatory conditions improved identification of inflammation-associated targets compared to using just the basal condition. This underscored the value of incorporating disease-relevant stimulations in perturbation experiments. Our results highlight the utility of scFMs for data-driven target nomination, emphasize the role of cellular state in regulatory responses, and provide a scalable, model-agnostic approach for ML-guided target discovery. This work offers a valuable community resource for advancing biological understanding of inflammatory-associated disease.

bioinformatics↗

bioRxiv2026

Single-cell spatially resolved transcriptomic characterization of the developing mouse cochlea

The cochlea, the sensory organ of hearing, functions as a frequency analyzer, analogous to a musical instrument. During development, while the medio-lateral axis supports differentiation of sensory cells and their surrounding supporting cells, the longitudinal axis underlies frequency-dependent properties of the cochlea. The combination of these two gene expression gradients defines unique physiological attributes of each cell intimately linked to its position within the cochlea. To determine which cochlear cell-types have a transcriptomic signature sensitive to these two gradients and identify the underlying gene regulatory networks, we took advantage of the advent of spatial single cell transcriptomics methodologies. We therefore generated a spatial transcriptomic atlas reaching single cell resolution based on the Visium HD technique, a sequencing-based technology that employ arrays of spatially barcoded probes to capture RNA molecules unbiasedly from histological tissue sections. Spatial transcriptional changes during embryonic stages, E14 and E16, as well as during postnatal development, P1 and P8, were investigated. Based on this dataset, not only cell-type assignment in single cell RNA-seq experiments could be validated, but the classification for some cell-types could be refined. Gradients of gene expression along the medio-lateral and longitudinal axes in multiple cell-types together with their temporal dynamics across development were also uncovered. Altogether, this atlas paves the way for deciphering gene regulatory networks controlling gene expression as a function of position in the cochlear cell types, providing a valuable resource for the design of efficient, robust and safe gene therapy strategies.

cell biology↗

bioRxiv2019

Macromolecular and electrical coupling between inner hair cells in the rodent cochlea

Inner hair cells (IHCs) are the primary receptors for hearing. They are housed in the cochlea and convey sound information to the brain via synapses with the auditory nerve. IHCs have been thought to be electrically and metabolically independent from each other. We report that, upon developmental maturation, 30% of the IHCs are electrochemically coupled in mini-syncytia. This coupling permits transfer of fluorescently-labeled metabolites and macromolecular tracers. The membrane capacitance, Ca2+-current, and resting current increase with the number of dye-coupled IHCs. Dual voltage-clamp experiments substantiate low resistance electrical coupling. Pharmacology and tracer permeability rule out coupling by gap junctions and purinoceptors. 3D-electron-microscopy indicates instead that IHCs are coupled by membrane fusion sites. Consequently, depolarization of one IHC triggers presynaptic Ca2+-influx at active zones in the entire mini-syncytium. Based on our findings and modeling, we propose that IHC-mini-syncytia enhance sensitivity and reliability of cochlear sound encoding.

neuroscience↗