The loss of pancreatic β-cell identity emerges as an important feature of type 2 diabetes development, but the molecular mechanisms are still elusive. Here, we explore the cellautonomous role of the cell cycle regulator and transcription factor E2F1 in the maintenance of β-cell identity, insulin secretion and glucose homeostasis. We show that the β-cell-specific loss of E2f1 function in mice triggers glucose intolerance associated with defective insulin secretion, an altered endocrine cell mass, a downregulation of many β-cell genes and a concomitant increase of non-β-cell markers. Mechanistically, the epigenomic profiling of promoters of these non-β-cell upregulated genes identified an enrichment of bivalent H3K4me3/H3K27me3 or H3K27me3 marks. Conversely, promoters of downregulated genes were enriched in active chromatin H3K4me3 and H3K27ac histone marks. We find that specific E2f1 transcriptional, cistromic and epigenomic signatures are associated with these β-cell dysfunctions, with E2F1 directly regulating several β-cell genes at the chromatin level. Finally, the pharmacological inhibition of E2F transcriptional activity in human islets also impairs insulin secretion and the expression of β-cell identity genes. Our data suggest that E2F1 is critical for maintaining β-cell identity and function through a sustained control of β-cell and non β-cell transcriptional programs.

中文翻译：

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β 细胞特异性 E2f1 缺陷会损害葡萄糖稳态、β 细胞特性和胰岛素分泌


胰腺β细胞身份的丧失是2型糖尿病发展的一个重要特征，但其分子机制仍不清楚。在这里，我们探讨了细胞周期调节剂和转录因子 E2F1 在维持 β 细胞身份、胰岛素分泌和葡萄糖稳态中的细胞自主作用。我们发现，小鼠中 β 细胞特异性 E2f1 功能丧失会引发与胰岛素分泌缺陷、内分泌细胞量改变、许多 β 细胞基因下调以及非 β 细胞标记物随之增加相关的葡萄糖不耐受。从机制上讲，这些非 β 细胞上调基因的启动子的表观基因组分析鉴定出二价 H3K4me3/H3K27me3 或 H3K27me3 标记的富集。相反，下调基因的启动子富含活性染色质 H3K4me3 和 H3K27ac 组蛋白标记。我们发现特定的 E2f1 转录、顺反体和表观基因组特征与这些 β 细胞功能障碍相关，E2F1 在染色质水平直接调节多个 β 细胞基因。最后，对人胰岛中 E2F 转录活性的药理抑制也会损害胰岛素分泌和 β 细胞识别基因的表达。我们的数据表明，E2F1 通过持续控制 β 细胞和非 β 细胞转录程序，对于维持 β 细胞身份和功能至关重要。