Biochimica et biophysica acta. Molecular basis of disease · 2026
Xist-mediated B cell modulation: Implications for immune dysregulation in T1DM.
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Guo Yingxue, Lei Lin, Che Guanghua, Gao Hang, Hu Qibo
Аннотация
RATIONALE: Type 1 diabetes mellitus (T1DM) involves immune-mediated destruction of pancreatic β cells, but the role of B cells in the islet immune microenvironment remains unclear. This study investigated how the long non-coding RNA X-inactive specific transcript (Xist) regulates islet immunity during T1DM progression.
METHODS: Single-cell RNA sequencing of non-obese diabetic (NOD) mice was used to characterize dynamic changes in islet immune cells. RNA pull-down, RNA immunoprecipitation, and ChIP-qPCR were performed to define the epigenetic mechanism of Xist and assess H3K27 acetylation at target gene promoters. In vitro co-culture systems and lentiviral intervention models were used to evaluate the effects of Xist-HDAC3 modulation on immune activation and islet injury.
RESULTS: Xist was specifically upregulated in pancreatic islet B cells during T1DM progression and was positively associated with B-cell activation and pro-inflammatory cytokine production. Mechanistically, Xist interacted with HDAC3 and altered H3K27ac levels at the promoters of CD40 and CD80, leading to their upregulation and enhancing B-cell antigen presentation and immunostimulatory capacity. This promoted CD8+ T-cell activation and the spread of islet inflammation. Modulation of the Xist-HDAC3 axis in vivo reduced immune-mediated injury, preserved islet structure, and improved glycemic control. In vitro findings further confirmed that Xist is a key regulator of B cell-mediated T-cell activation.
CONCLUSIONS: In T1DM, the present findings suggest a strong correlation between Xist expression and B-cell activation. Supported by in vitro and in vivo models, these data propose a potential mechanism in which Xist may influence B-cell immune dysregulation through HDAC3-mediated epigenetic pathways.
METHODS: Single-cell RNA sequencing of non-obese diabetic (NOD) mice was used to characterize dynamic changes in islet immune cells. RNA pull-down, RNA immunoprecipitation, and ChIP-qPCR were performed to define the epigenetic mechanism of Xist and assess H3K27 acetylation at target gene promoters. In vitro co-culture systems and lentiviral intervention models were used to evaluate the effects of Xist-HDAC3 modulation on immune activation and islet injury.
RESULTS: Xist was specifically upregulated in pancreatic islet B cells during T1DM progression and was positively associated with B-cell activation and pro-inflammatory cytokine production. Mechanistically, Xist interacted with HDAC3 and altered H3K27ac levels at the promoters of CD40 and CD80, leading to their upregulation and enhancing B-cell antigen presentation and immunostimulatory capacity. This promoted CD8+ T-cell activation and the spread of islet inflammation. Modulation of the Xist-HDAC3 axis in vivo reduced immune-mediated injury, preserved islet structure, and improved glycemic control. In vitro findings further confirmed that Xist is a key regulator of B cell-mediated T-cell activation.
CONCLUSIONS: In T1DM, the present findings suggest a strong correlation between Xist expression and B-cell activation. Supported by in vitro and in vivo models, these data propose a potential mechanism in which Xist may influence B-cell immune dysregulation through HDAC3-mediated epigenetic pathways.