Biology subjects

Tse, H. M.

Publications and source records attributed to Tse, H. M..

5 recordsLinked to original sources

bioRxiv2026

Brca1 heterozygosity leads to hepatic steatosis in male and female mice despite sexually dimorphic effects on systemic metabolism

Carrying a germline mutation in BRCA1 is associated with an increased risk of several cancers, including breast and ovarian. Our recent work has demonstrated that obesity is associated with elevated levels of DNA damage in breast glands in this high-risk population. BRCA1 is a canonical tumor suppressor gene primarily recognized for its role in DNA damage repair, yet emerging evidence suggests broader functions in metabolic regulation. To determine whether heterozygous loss of Brca1, as seen in individuals who carry a germline mutation, modifies susceptibility to diet-induced metabolic dysfunction in a sex-dependent manner, we subjected wild-type (WT) and Brca1+/- mice of both sexes to a high-fat diet (HFD) and performed longitudinal metabolic phenotyping. Female Brca1+/- mice exhibited pronounced obesity, increased adiposity, hyperinsulinemia, and impaired glucose tolerance. In contrast, male Brca1+/- mice showed modest resistance to HFD-induced weight gain and displayed improved glucose tolerance compared to WT controls. Notably, Brca1 heterozygosity led to more severe hepatic steatosis with HFD, indicating a shared susceptibility to liver lipid accumulation despite divergent systemic outcomes. In females, steatosis was associated with reduced mitochondrial respiratory complex IV activity and transcriptional remodeling that favored lipid storage. Treatment with the dual GLP1/GIP receptor agonist tirzepatide ameliorated systemic metabolic dysfunction and hepatic steatosis in HFD-fed female Brca1+/- mice. These findings identify Brca1 heterozygosity as a modifier of metabolic disease risk, expanding BRCA1 biology beyond tumor suppression. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=87 SRC="FIGDIR/small/708005v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@17f9592org.highwire.dtl.DTLVardef@134c2c2org.highwire.dtl.DTLVardef@de69d8org.highwire.dtl.DTLVardef@1f6f1af_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

Protective IFIH1 variant reduces immune-mediated islet stress and dysfunction in a type 1 diabetes genetic background

Genome-wide association studies (GWAS) have linked dozens of genetic loci to type 1 diabetes (T1D). The IFIH1 gene, which encodes the double-stranded RNA sensor MDA5, is one such locus. The E627* single nucleotide polymorphism (SNP) in IFIH1 is associated with protection against T1D, while the A946T variant is linked to increased risk. While the E627* variant has been shown to result in a truncated protein and dampen type I interferon (IFN) signaling, its specific role in human pancreatic islet health and function remains unclear. We hypothesized that MDA5627* would protect islet cells from stress-induced dysfunction, identity loss, and cell death. Using CRISPR-Cas9 technology, we introduced the E627* and A946T variants into human pluripotent stem cells (hPSCs) derived from a T1D patient. We differentiated these hPSCs into stem cell-derived islets (SC-islets) and treated them with IFN, poly(I:C), and coxsackievirus B3, an enterovirus implicated in T1D pathogenesis. Using single-cell RNA sequencing and an array of functional assays, we investigated the variant impact on both whole SC-islets and their individual cell populations. Our analysis revealed that SC-islets, and their {beta}, , and {delta} cell subpopulations, harboring the MDA5627* variant exhibit an attenuated immune response to the various stressors compared to MDA5946T cells. We also report unique, cell-type-specific transcriptional responses that vary across variants. Notably, MDA5627* SC-islets showed reduced apoptosis rates and viral genome expression, as well as attenuated negative effects on mitochondrial function and insulin secretion in response to stress. Overall, our findings demonstrate that a clinically relevant MDA5 variant confers protection by dampening stress-mediated transcriptional responses, reducing cell dysfunction, and preventing apoptosis. These insights provide a mechanistic framework for understanding T1D pathogenesis and offer new avenues for developing preventative therapies.

cell biology↗

bioRxiv2025

Islet-intrinsic sex differences in inflammatory signaling contribute to autoimmune diabetes susceptibility

Whereas most autoimmune diseases exhibit female predominance, type 1 diabetes (T1D) occurs more frequently in males after puberty, suggesting a role for sex hormones in disease modification. Because islet {beta} cells actively shape local immune responses, we hypothesized that sex-specific islet responses to inflammation contribute to this disparity. Using transcriptomic and proteomic analyses of human islets from male and female donors, we found that male islets exhibit a more aggressive response to proinflammatory cytokines, characterized by greater induction of interferon signaling and suppression of developmental signaling compared to female islets. Treatment of human islets and mouse {beta} cells with the sex hormone 17{beta}-estradiol (E2) suppressed inflammatory signaling and markers of {beta}-cell maturity while enhancing developmental gene programs. Complementary studies in non-obese diabetic (NOD) mice showed that E2 treatment reduces diabetes incidence and limits progression to severe insulitis. Islet single-cell RNA sequencing revealed that E2 treatment of NOD mice suppresses interferon signaling, chemokine production, and antigen presentation in {beta} cells, while reducing activation and cytotoxicity pathways in immune cells. In co-culture studies in vitro, E2 pretreatment of mouse islets reduces subsequent activation of T cells, and in an aggressive adoptive transfer model in vivo, E2 pretreatment of the recipient mice was found to attenuate hyperglycemia. These findings support a model in which E2-mediated {beta}-cell reprogramming reduces {beta}-cell immunogenicity and promotes local immune tolerance, offering mechanistic insight into sex-biased T1D susceptibility.

cell biology↗

bioRxiv2024

Coxsackievirus B infection invokes unique cell-type specific responses in primary human pancreatic islets

Coxsackievirus B (CVB) infection has long been considered an environmental factor precipitating Type 1 diabetes (T1D), an autoimmune disease marked by loss of insulin-producing {beta} cells within pancreatic islets. Previous studies have shown CVB infection negatively impacts islet function and viability but do not report on how virus infection individually affects the multiple cell types present in human primary islets. Therefore, we hypothesized that the various islet cell populations have unique transcriptional responses to CVB infection. Here, we performed single-cell RNA sequencing on human cadaveric islets treated with either CVB or poly(I:C), a viral mimic, for 24 and 48 hours. Our global analysis reveals CVB differentially induces dynamic transcriptional changes associated with multiple cell processes and functions over time whereas poly(I:C) promotes an immune response that progressively increases with treatment duration. At the single-cell resolution, we find CVB infects all islet cell types at similar rates yet induces unique cell-type specific transcriptional responses with {beta}, , and ductal cells having the strongest response. Sequencing and functional data suggest that CVB negatively impacts mitochondrial respiration and morphology in distinct ways in {beta} and cells, while also promoting the generation of reactive oxygen species. We also observe an increase in the expression of the long-noncoding RNA MIR7-3HG in {beta} cells with high viral titers and reveal its knockdown reduces gene expression of viral proteins as well as apoptosis in stem cell-derived islets. Together, these findings demonstrate a cell-specific transcriptional, temporal, and functional response to CVB infection and provide new insights into the relationship between CVB infection and T1D.

cell biology↗

bioRxiv2021

NADPH Oxidase 2 Derived Reactive Oxygen Species Promote CD8+ T cell Effector Function

Oxidants participate in lymphocyte activation and function. We previously demonstrated that eliminating the activity of NADPH oxidase 2 (NOX2) significantly impaired the effectiveness of autoreactive CD8+ cytotoxic T lymphocytes (CTL). However, the molecular mechanisms impacting CTL function remain unknown. Here, we studied the role of NOX2 in both non-obese diabetic (NOD) mouse and human CTL function. Genetic ablation or chemical inhibition of NOX2 in CTL significantly suppressed activation-induced expression of the transcription factor T-bet, the master transcription factor of the Tc1 cell lineage, and T-bet target effectors genes such as IFN{gamma} and granzyme B. Inhibition of NOX2 in both human and mouse CTL prevented target cell lysis. We identified that superoxide generated by NOX2 must be converted into hydrogen peroxide to transduce the redox signal in CTL. Further, we show that NOX2-generated oxidants deactivate the Tumor Suppressor Complex leading to mTOR complex 1 activation and CTL effector function. These results indicate that NOX2 plays a non-redundant role in T cell receptor-mediated CTL effector function.

immunology↗