Biology subjects

Chua, M.

Publications and source records attributed to Chua, M..

5 recordsLinked to original sources

bioRxiv2026

Region-specific molecular regulatory programs define epithelial identity, progenitor states, and mucus homeostasis in human distal airways

Small distal airways differ from proximal large airways in structure, airflow dynamics, and epithelial composition, and represent a central site of muco-obstructive lung disease pathogenesis. However, due in part to their inaccessibility, the molecular mechanisms that establish regional epithelial identity and govern mucociliary defense in distal airway epithelia remain poorly defined. Here, we integrate transcriptomic, secretomic, and chromatin accessibility analyses of matched primary human large and small airway epithelial cultures to define region-specific regulatory networks. We identify distal airway-specific transcriptional and chromatin programs required for maintaining epithelial identity and mucus homeostasis. Loss of NKX2-1 impairs distal airway secretory cell (DASC) differentiation and shifts mucus properties toward a disease-associated state. Lineage-resolved organoid assays identify an NKX2-1-high distal airway basal cell population with hybrid basal-secretory features as a selective progenitor for DASCs. Collectively, these findings establish a molecular framework for distal airway epithelial biology and define mechanisms regulating region-specific mucociliary host defense.

Cell Biology↗

bioRxiv2025

DINOcell: Learning Generalizable Perturbation Effects through Self-Distillation

AO_SCPLOWBSTRACTC_SCPLOWPredicting cellular responses to therapeutics is a promising approach for novel target discovery. However, state-of-the-art computational models designed to predict perturbation effects struggle to generalize and outperform simple baselines. We present DINOcell, a weakly supervised framework that adapts self-distillation to single-cell transcriptomics for predicting perturbation effects. We demonstrate that DINOcell outperforms baselines in predicting the effects of single gene perturbations. Furthermore, DINOcell accurately predicts non-additive effects of combination perturbations, indicating its capacity to model complex genetic interactions. Finally, we show that DINOcell learns representations that capture biological signals and is a promising, generalizable approach for in silico perturbation modeling, providing a valuable tool for accelerating therapeutic target discovery.

bioinformatics↗

bioRxiv2024

Dysregulated Airway Host Defense in Hyper IgE Syndrome due to STAT3 Mutations

RationaleHyper IgE syndrome (STAT3-HIES), also known as Jobs syndrome, is a rare immunodeficiency disease typically caused by dominant-negative STAT3 mutations. STAT3-HIES syndrome is characterized by chronic pulmonary infection and inflammation, suggesting impairment of pulmonary innate host defense. ObjectivesTo identify airway epithelial host defense defects consequent to STAT3 mutations that, in addition to reported mutant STAT3 immunologic abnormalities, produce pulmonary infection. MethodsSTAT3-HIES sputum was evaluated for biochemical/biophysical properties. STAT3-HIES excised lungs were harvested for histology; bronchial brush samples were collected for RNA sequencing and in vitro culture. A STAT3-HIES-specific mutation (R382W), expressed by lentiviruses, and a STAT3 knockout, generated by CRISPR/Cas9, were maintained in normal human bronchial epithelia under basal or inflammatory (IL1{beta}) conditions. Effects of STAT3 deficiency on transcriptomics, and epithelial ion channel, secretory, antimicrobial, and ciliary functions were assessed. Measurements and Main ResultsMucus concentrations and viscoelasticity were increased in STAT3-HIES sputum. STAT3-HIES excised lungs exhibited mucus obstruction and elevated IL1{beta} expression. STAT3 deficiency impaired CFTR-dependent fluid and mucin secretion, inhibited expression of antimicrobial peptides, cytokines, and chemokines, and acidified airway surface liquid at baseline and post-IL1{beta} exposure in vitro. Notably, mutant STAT3 suppressed IL1R1 expression. STAT3 mutations also inhibited ciliogenesis in vivo and impaired mucociliary transport in vitro, a process mediated via HES6 suppression. Administration of a {gamma}-secretase inhibitor increased HES6 expression and improved ciliogenesis in STAT3 R382W mutant cells. ConclusionsSTAT3 dysfunction leads to multi-component defects in airway epithelial innate defense, which, in conjunction with STAT3-HIES immune deficiency, contributes to chronic pulmonary infection.

cell biology↗

bioRxiv2021

Dispersal of southern elephant seals (Mirounga leonina) from Davis Base, Antarctica: Combining population genetics and tracking data

Marine animals such as the southern elephant seal (Mirounga leonina) rely on a productive marine environment and are vulnerable to oceanic changes that can affect their reproduction and survival rates. Davis Base, Antarctica, acts as a moulting site for southern elephant seals that forage in Prydz Bay, but the genetic diversity and natal source populations of these seals has not been characterized. Determining the genetic diversity of moulting populations like this one provides essential information on seal dispersal, inter-population mixing, and foraging behaviours. In this study, we combined genetic and animal tracking data on these moulting seals to identify levels of genetic diversity, natal source population, and movement behaviours during foraging and haul-out periods. Using mitochondrial sequence data, we identified two major breeding lineages of seals at Davis Base. We found that the majority of the seals originated from breeding stocks within the South Atlantic Ocean and South Indian Ocean. One seal was grouped with the Macquarie Island breeding stock (South Pacific Ocean). The Macquarie Island population, unlike the other two stocks, is decreasing in size. Tracking data revealed long-distance foraging activity of the Macquarie Island seal around Crozet Islands. We speculate that changes to the Antarctic marine environment have resulted in a shift in foraging and dispersal strategies, which subsequently affects seal population growth rates. These findings have implications for conservation management plans aimed at improving the population status of the southern elephant seal.

ecology↗

bioRxiv2021

Destabilization of β-cell FIT2 by saturated fatty acids contribute to ER stress and diabetes

Western type diets are linked to obesity and diabetes partly because of their high saturated fatty acid (SFA) content. We found that SFAs, but not unsaturated fatty acids (USFAs), reduced the number of lipid droplets (LDs) within pancreatic {beta}-cells. Mechanistically, SFAs but not USFAs disabled LD biogenesis by inducing palmitoylation and subsequent ERAD-C mediated degradation of LD formation protein, Fat storage-Inducing Transmembrane protein 2 (FIT2). Targeted ablation of FIT2 reduced {beta}-cell LD numbers, lowered {beta}-cell ATP levels, reduced Ca2+ signaling, downregulated {beta}-cell transcription factors (RNA sequencing analysis), and exacerbated diet-induced diabetes in mice. Subsequent mass spectrometry studies revealed increased C16:0 ceramide accumulation in islets of mice lacking {beta}-cell FIT2 under lipotoxic conditions. Inhibition of ceramide synthases ameliorated the enhanced ER stress. Overexpression of FIT2 increased number of intracellular LDs and rescued SFA-induced ER-stress and apoptosis thereby highlighting the protective role of FIT2 and LDs against {beta}-cell lipotoxicity and diet-induced diabetes.

biochemistry↗