Effects of Beta Cell Specific Smc3 Loss on Islet Cell Identity and Inflammation

Overview

Diabetes is characterized by dysregulated glucose homeostasis due to reduced quantity and quality of functional insulin-producing beta-cells in the pancreas. Accumulation of DNA damage in pancreatic beta-cells is considered a key driver of this functional impairment, yet the mechanisms that exacerbate DNA damage in diabetes pathogenesis remain poorly understood. Cohesin is a nuclear protein complex, mediating various cellular functions such as DNA compaction, sister chromatid cohesion, and enhancer-promoter interactions. Furthermore, Cohesin plays a critical role in the DNA damage response, with recent data demonstrating that Cohesin protects beta-cells against DNA damage. Prior studies show that beta-cells are unusually vulnerable to DNA damage under diabetic conditions, leading to their dysfunction or apoptosis. In addition, preliminary data from our lab indicate that the expression level of Cohesin is reduced in diabetic beta-cells. In this regard, this project investigated the effects of beta-cell–specific Cohesin loss using a conditional knockout (KO) mouse model of Smc3, a component of the Cohesin complex. This project aimed to clarify how Cohesin preserves genomic integrity in beta-cells, in order to establish a link between genomic instability and diabetes pathogenesis. Therefore, I hypothesized that beta-cell specific Cohesin loss causes increased co-expression of insulin and glucagon in islet cells, an indication of a loss of cell identity. I further hypothesize that the loss of Cohesin function contributes to an elevated presence of CD45+ cells within islets, a marker for tissue inflammation. Such a loss of cell identity and an elevation of inflammation are expected to exacerbate the progression of diabetes. Smc3fl/fl conditional KO mouse was generated using the Cre-LoxP recombination system; Ins1-CreThor was utilized for β-cell–specific deletion. Smc3 is a key component of the Cohesin complex that regulates various chromosomal activities, thus its deletion impairs Cohesin functions. Genetically normal mice of the same strain (wildtype (WT)) were used as a control. A standard immunofluorescence protocol was used to detect various proteins of interest such as insulin, glucagon, somatostatin, and CD45 in pancreatic sections. Pancreata (n=24) were isolated from 6-month-old KO and WT mice, formalin-fixed, and paraffin-embedded into blocks. Sectioned using a microtome, the pancreatic samples were transferred onto glass slides (2 sections per slide), yielding a total of 48 sections across 24 samples. One section was stained for insulin, glucagon, and CD45, while the other section was stained for insulin and somatostatin. This arrangement allowed for simultaneous analysis of endocrine cell types and immune cells in the adjacent sections. Slides were examined using a Leica DM6B microscope equipped with a HC PL FLUOTAR 20×/0.40 NA objective and imaged using Leica Application Suite X. Each image contained 1-5 islets in a frame; quantifications were stratified by islet, and a cumulative total was calculated for each sample. Images were processed using the ImageJ software, and data were tabulated using Microsoft Excel. The statistical significance of differences was determined by a one-way ANOVA with Fisher’s post-hoc test for experiments with repeated measurements. Compared to the WT mice, samples with the beta-cell specific knockout of Smc3, which leads to a functional loss of Cohesin, yielded higher genomic instability; results showed an increase in bihormonal cell population, both for the glucagon-positive alpha/insulin-positive beta-cell pool (approximately 850%, p<0.01 in males, approximately 1400%, p<0.001 in females) and somatostatin-positive delta/insulin-positive beta-cell pool (approximately 900%, ns in males, approximately 900%, p<0.0001 in females). Furthermore, early immune infiltration, features associated with beta-cell fragility in diabetes, was also observed in the KO mice, identified by a noticeably increased population of CD45+ cells in the islets. These results suggest that Cohesin plays a significant role in chromatin organization and transcriptional programs required for islet cell stability, and that its loss disrupts these processes in ways that promote both genomic instability and inflammation. This provides potential explanations for the corresponding characteristics commonly observed within diabetes pathogenesis, such as autoimmunity. Interestingly, this genomic instability mirrors recent observations in normal aging. It has been shown that a subset of beta-cells naturally exhibits increased co-expression of both insulin (INS) and glucagon (GCG) mRNA in an age-dependent manner, reflecting age-dependent transcriptional instability. Whether driven by Cohesin loss or aging, the bihormonal secretion indicates that disruptions in chromatin organization or transcriptional regulation can destabilize islet cell identity. This similarity suggests that Cohesin functions as a molecular safeguard against such transcriptional drift, reinforcing the idea that its loss promotes instability at the same level as an aging phenotype within the pancreatic islet. Current therapeutic strategies for diabetes largely target the downstream consequences of diabetes, such as a focus on hyperglycemia or autoimmunity, rather than addressing the intrinsic vulnerability of beta-cells themselves. Medications like insulin, GLP-1 receptor agonists, and immunomodulators manage the symptoms or blunt the immune attack, which leaves the underlying genomic instability of beta-cells unaddressed. In contrast, the findings from this study implicate Cohesin-mediated chromatin organization as a critical factor of beta-cell identity and integrity. By directly linking DNA repair and epigenetic maintenance to beta-cell function, this work highlights the opening of a novel pathway for therapeutic intervention. Stabilizing the epigenome to prevent beta-cell dedifferentiation and immune activation could potentially improve the lives of millions who live with diabetes. This study suggests that targeting epigenetic pathways could complement existing treatments such as insulin supplementation, offering a proactive approach that preserves intrinsic beta-cell integrity rather than only managing the downstream effects of diabetes. Showing the mechanistic link between DNA damage and diabetes pathogenesis, this study also provides evidence that impaired chromatin regulation can contribute to beta-cell dysfunction in both Type 1 and Type 2 diabetes. Future research should confirm this mechanism in human pancreas as well. The identification of the specific genomic regions affected by Cohesin loss will allow us to evaluate whether enhancing Cohesin function or DNA repair can preserve the beta-cell integrity, hence mitigating the development or symptoms of diabetes. While the observed results from this study were statistically significant in the majority of the experiments, it's important to acknowledge that these initial conclusions are drawn from a limited number of animals and should be validated in larger cohorts to ensure their generalizability. Furthermore, additional investigation of these phenomena in older mice which typically exhibit a greater degree of DNA damage/repair may reveal link between aging and susceptibility to diabetes. Nevertheless, this work provides strong evidence for a novel potential mechanism of diabetes progression. This suggests that therapeutic strategies aimed not just at managing autoimmunity or metabolic stress, but at reinforcing the intrinsic genomic integrity of the beta-cell itself, could represent a novel approach to prevent or reverse the disease.

Competition history

• CSEF 2026 Biochemistry/ Molecular Biology (Senior Division) · Entry S-04-22

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