Biology subjects

Chua, R. L.

Publications and source records attributed to Chua, R. L..

3 recordsLinked to original sources

bioRxiv2025

Latent plasticity of the human pancreas across development, health, and disease.

The pancreas plays a central role in major human diseases, yet our understanding of its cellular diversity and plasticity remains incomplete. Here, we present a single-cell multiomics atlas of the human pancreas, profiling over four million cells and nuclei from 57 donors across fetal development, adult homeostasis, and type 2 diabetes (T2D). Integrating sc/snRNA-seq, snATAC-seq, VASA-seq, spatial transcriptomics (Xenium), and multiplexed proteomics (CODEX), we resolve gene expression, chromatin accessibility, and spatial organization at high resolution. We identify transcriptionally plastic centroacinar-like cells (pCACs) in adults with fetal-like features, delineate endocrine and exocrine lineage trajectories during development, and uncover HNF1A-defined beta cell epigenetic states. In T2D, we observe shifts in beta cell subtypes and altered regulatory programs. Glucose perturbation of healthy islets reveals cell-type-specific adaptation and stress responses. This atlas provides a foundational framework to understand pancreas biology and the role of cellular plasticity in regeneration and disease.

genomics↗

bioRxiv2025

Long-read single-cell RNA sequencing uncovers cell-type specific transcript regulation in COVID-19

SARS-CoV-2 infection leads to extensive host transcriptomic changes, but the role of alternative splicing in shaping the immune response remains underexplored. Here, we present the first application of long-read single-cell RNA sequencing on nasopharyngeal swabs from COVID-19 patients and healthy controls to resolve transcript-level changes across cell types. Our analysis identified major epithelial cell types and pronounced immune infiltration, with cell-type annotations concordant with those from short-read data. By enabling isoform-level resolution, our nanopore sequencing approach revealed cell-type specific alternative splicing, undetectable with short-read sequencing. For example, although gene-level expression of the key immune and apoptosis regulators, IFNAR2 and FAIM, did not differ between COVID-19 patients and healthy controls we identified marked shifts in isoform usage. Between moderate and critical cases, we observed cell-type specific differential transcript usage in the T cell signaling kinase FYN and the immune-regulatory transcription factor IRF2. As some of these splicing alterations yield functionally distinct isoforms, we hypothesize that alternative splicing modulates immune signaling and apoptosis, fine-tuning the host response to SARS-CoV-2 infection. Our study demonstrates the unique power of long-read single-cell transcriptomics to uncover isoform-resolved regulatory changes, offering novel insights into the role of alternative splicing in shaping immune responses to viral infections.

genomics↗

bioRxiv2020

SARS-CoV-2 receptor ACE2 and TMPRSS2 are predominantly expressed in a transient secretory cell type in subsegmental bronchial branches

The SARS-CoV-2 pandemic affecting the human respiratory system severely challenges public health and urgently demands for increasing our understanding of COVID-19 pathogenesis, especially host factors facilitating virus infection and replication. SARS-CoV-2 was reported to enter cells via binding to ACE2, followed by its priming by TMPRSS2. Here, we investigate ACE2 and TMPRSS2 expression levels and their distribution across cell types in lung tissue (twelve donors, 39,778 cells) and in cells derived from subsegmental bronchial branches (four donors, 17,521 cells) by single nuclei and single cell RNA sequencing, respectively. While TMPRSS2 is expressed in both tissues, in the subsegmental bronchial branches ACE2 is predominantly expressed in a transient secretory cell type. Interestingly, these transiently differentiating cells show an enrichment for pathways related to RHO GTPase function and viral processes suggesting increased vulnerability for SARS-CoV-2 infection. Our data provide a rich resource for future investigations of COVID-19 infection and pathogenesis.

genomics↗