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Repression of latent NF-κB enhancers by PDX1 regulates β cell functional heterogeneity
Cell Metabolism ( IF 27.7 ) Pub Date : 2024-01-02 , DOI: 10.1016/j.cmet.2023.11.018 Benjamin J Weidemann 1 , Biliana Marcheva 1 , Mikoto Kobayashi 1 , Chiaki Omura 1 , Marsha V Newman 1 , Yumiko Kobayashi 1 , Nathan J Waldeck 1 , Mark Perelis 2 , Louise Lantier 3 , Owen P McGuinness 3 , Kathryn Moynihan Ramsey 1 , Roland W Stein 4 , Joseph Bass 1
Cell Metabolism ( IF 27.7 ) Pub Date : 2024-01-02 , DOI: 10.1016/j.cmet.2023.11.018 Benjamin J Weidemann 1 , Biliana Marcheva 1 , Mikoto Kobayashi 1 , Chiaki Omura 1 , Marsha V Newman 1 , Yumiko Kobayashi 1 , Nathan J Waldeck 1 , Mark Perelis 2 , Louise Lantier 3 , Owen P McGuinness 3 , Kathryn Moynihan Ramsey 1 , Roland W Stein 4 , Joseph Bass 1
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Interactions between lineage-determining and activity-dependent transcription factors determine single-cell identity and function within multicellular tissues through incompletely known mechanisms. By assembling a single-cell atlas of chromatin state within human islets, we identified β cell subtypes governed by either high or low activity of the lineage-determining factor pancreatic duodenal homeobox-1 (PDX1). β cells with reduced PDX1 activity displayed increased chromatin accessibility at latent nuclear factor κB (NF-κB) enhancers. hypomorphic mice exhibited de-repression of NF-κB and impaired glucose tolerance at night. Three-dimensional analyses in tandem with chromatin immunoprecipitation (ChIP) sequencing revealed that PDX1 silences NF-κB at circadian and inflammatory enhancers through long-range chromatin contacts involving SIN3A. Conversely, ablation in β cells disrupted genome-wide PDX1 and NF-κB DNA binding. Finally, antagonizing the interleukin (IL)-1β receptor, an NF-κB target, improved insulin secretion in hypomorphic islets. Our studies reveal functional subtypes of single β cells defined by a gradient in PDX1 activity and identify NF-κB as a target for insulinotropic therapy.
中文翻译：
PDX1 抑制潜在 NF-κB 增强子调节 β 细胞功能异质性
谱系决定因子和活性依赖性转录因子之间的相互作用通过不完全已知的机制决定多细胞组织内的单细胞身份和功能。通过组装人类胰岛内染色质状态的单细胞图谱，我们鉴定了由谱系决定因子胰腺十二指肠同源盒-1 (PDX1) 的高活性或低活性控制的 β 细胞亚型。 PDX1 活性降低的 β 细胞显示出潜在核因子 κB (NF-κB) 增强子染色质可及性增加。低效态小鼠表现出 NF-κB 去抑制和夜间糖耐量受损。三维分析与染色质免疫沉淀 (ChIP) 测序相结合显示，PDX1 通过涉及 SIN3A 的长程染色质接触来沉默昼夜节律和炎症增强子中的 NF-κB。相反，β细胞的消融破坏了全基因组 PDX1 和 NF-κB DNA 结合。最后，拮抗白细胞介素 (IL)-1β 受体（一种 NF-κB 靶标）可改善低效胰岛的胰岛素分泌。我们的研究揭示了由 PDX1 活性梯度定义的单个 β 细胞的功能亚型，并将 NF-κB 确定为促胰岛素治疗的靶点。
更新日期：2024-01-02
中文翻译：
PDX1 抑制潜在 NF-κB 增强子调节 β 细胞功能异质性
谱系决定因子和活性依赖性转录因子之间的相互作用通过不完全已知的机制决定多细胞组织内的单细胞身份和功能。通过组装人类胰岛内染色质状态的单细胞图谱，我们鉴定了由谱系决定因子胰腺十二指肠同源盒-1 (PDX1) 的高活性或低活性控制的 β 细胞亚型。 PDX1 活性降低的 β 细胞显示出潜在核因子 κB (NF-κB) 增强子染色质可及性增加。低效态小鼠表现出 NF-κB 去抑制和夜间糖耐量受损。三维分析与染色质免疫沉淀 (ChIP) 测序相结合显示，PDX1 通过涉及 SIN3A 的长程染色质接触来沉默昼夜节律和炎症增强子中的 NF-κB。相反，β细胞的消融破坏了全基因组 PDX1 和 NF-κB DNA 结合。最后，拮抗白细胞介素 (IL)-1β 受体（一种 NF-κB 靶标）可改善低效胰岛的胰岛素分泌。我们的研究揭示了由 PDX1 活性梯度定义的单个 β 细胞的功能亚型，并将 NF-κB 确定为促胰岛素治疗的靶点。
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