美国西北大学范伯格医学院Joseph Bass团队近期取得重要工作进展，他们研究提出，PDX1抑制潜在NF-κB增强子可调控β细胞功能异质性。相关研究成果2024年1月2日在线发表于《细胞—代谢》杂志上。

据介绍，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中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，研究人员确定了由谱系决定因子胰十二指肠同源盒-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细胞在潜在核因子κB（NF-κB）增强子上表现出染色质可及性增加。Pdx1亚形态小鼠在夜间表现出对NF-κB的去抑制和糖耐量受损。

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，在昼夜节律和炎症增强因子处沉默NF-κB。相反，β细胞中的Bmal1消融破坏了全基因组PDX1和NF-κB 的DNA结合。最后，拮抗白细胞介素（IL）-1β受体（NF-κB靶点）可改善Pdx1低形态胰岛的胰岛素分泌。

总之，这一研究揭示了由PDX1活性梯度定义的单个β细胞的功能亚型，并确定NF-κB是促胰岛素治疗的靶点。

附：英文原文

Title: Repression of latent NF-κB enhancers by PDX1 regulates β cell functional heterogeneity

Author: Benjamin J. Weidemann, Biliana Marcheva, Mikoto Kobayashi, Chiaki Omura, Marsha V. Newman, Yumiko Kobayashi, Nathan J. Waldeck, Mark Perelis, Louise Lantier, Owen P. McGuinness, Kathryn Moynihan Ramsey, Roland W. Stein, Joseph Bass

Issue&Volume: 2024/01/02

Abstract: 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. Pdx1 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, Bmal1 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 Pdx1 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.

DOI: 10.1016/j.cmet.2023.11.018

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00451-5