Wang, Liu

Accumulation of DNA damage drives β-cell dysfunction, senescence, and death in type 1 and type 2 diabetes. Although α-cell dysfunction also contributes to disease pathology, α-cells remain remarkably resistant to senescence and increased cell death under diabetogenic stress. The mechanisms underlying these differential responses to diabetogenic stress, particularly differences in their DNA damage vulnerability, remain unclear. We demonstrate that replication introduces a window of genomic vulnerability in both α- and β-cells during neonatal growth, with α-cells exhibiting higher replication rates and DNA damage. We show that neonatal β-cells resolve DNA damage more efficiently during mitosis and favor error-free repair, whereas α-cells compensate for their greater DNA-damage vulnerability through increased cellular turnover. Using mouse models of overnutrition and diabetes, we show that β-cells exhibit greater vulnerability to terminal DNA damage and impaired repair capacity under diabetogenic stress, with compensatory replication amplifying this vulnerability. We demonstrate that developmental and postnatal epigenetic programs shape the differential DNA damage vulnerability of postnatal β- and α-cells. Loss of de novo DNA methyltransferase Dnmt3a in pancreatic progenitors selectively increases the DNA damage vulnerability of β-cells from neonatal growth through adulthood. Complementing this developmental process, enhancer analyses reveal lineage-specific DNA damage response regulatory landscapes that are remodeled in β-cells under metabolic stress. Collectively, our findings uncover novel developmental mechanisms that shape the distinct DNA damage responses of postnatal β- and α-cells during growth and diabetes. Article Highlights Mechanisms underlying the differential susceptibility of pancreatic β- and α-cells to diabetogenic stress remain unclear. We investigated whether replication, repair fidelity, and developmental epigenetic programs determine the vulnerability of postnatal β- and α-cells to DNA damage, a key driver of β-cell failure in diabetes. Replication introduces DNA damage vulnerability in both neonatal β- and α-cells, yet β-cells resolve damage more efficiently. Loss of DNA methyltransferase 3a in pancreatic progenitors selectively heightens β-cell DNA damage vulnerability that persists into adulthood. Moreover, diabetogenic stress preferentially compromises β-cell repair fidelity. These findings reveal how developmental programs shape β-cell resilience and may influence lifelong diabetes risk.

Abstract In both type 1 and type 2 diabetes (T1D and T2D), insulin-producing β cells undergo progressive dysfunction due to inflammation, leading to impaired glucose responsiveness, dedifferentiation, and cell loss. While bile acid (BA) dysregulation under diabetic conditions is known to influence metabolic and inflammatory pathways, its mechanistic role in β cell regulation remains incompletely defined 1–3 . Here we show that bile acid sensor Farnesoid X receptor (FXR) and Bromodomain and Extra-Terminal motif (BET) signaling cooperatively regulates β cell inflammatory response and β cell identity. We identified the physiological protein-protein interaction between FXR and the bromodomain-containing protein 4 (BRD4) as a regulatory axis that protects against β cell dysfunction. We show that FXR activation by Fexaramine (Fex) together with BRD4 inhibition by JQ1 synergistically suppressed IL-1β-induced inflammation while also improving β cell identity and insulin secretion in both db/db model and high-fat diet (HFD) plus multi low-dose streptozotocin (MLD-STZ) model of diabetes. Importantly, this cooperative effect is abolished in β cell–specific FXR knockout (βFXRKO) mice, establishing that FXR is required for the functional synergy between these pathways in vivo . Mechanistically, structure-guided modeling and mutational analyses identified a direct interaction between FXR and the BD2 domain of BRD4, depending on specific lysine acetylation sites. Additionally, inhibition of the BD2 domain of BET combined with FXR activation markedly improved β cell survival in human T1D and T2D models established from human pluripotent stem cell (hPSC)-derived islet-like organoids (HILOs). Collectively, these findings establish a BA–bromodomain axis as a transcriptional interface linking metabolic signaling and chromatin regulation, and highlight FXR–BET targeting as a promising strategy to counter progressive β cell failure in diabetes.

Significance Glucocorticoids are widely prescribed antiinflammatory drugs that suppress inflammatory gene expression through activation of the glucocorticoid receptor (GR); however, the mechanisms of GR-mediated repression are not fully understood. We show here that bromodomain containing 9 (BRD9), a component of the SWI/SNF chromatin remodeling complex, modulates GR activity in bone marrow-derived macrophages. Loss of BRD9 activity in macrophages attenuated the response to liposaccharides and interferon inflammatory stimuli. Notably, BRD9 inhibition synergized with the synthetic glucocorticoid dexamethasone to suppress the inflammatory response in macrophages. Our data support a model in which BRD9 restricts GR binding at a subset of inflammatory related genes, and suggests that BRD9 inhibitors may increase the efficacy of glucocorticoids.