The physiological functions of many vital tissues and organs continue to mature after birth, but the genetic mechanisms governing this postnatal maturation remain an unsolved mystery. Human pancreatic β cells produce and secrete insulin in response to physiological cues like glucose, and these hallmark functions improve in the years after birth. This coincides with expression of the transcription factors SIX2 and SIX3, whose functions in native human β cells remain unknown. Here, we show that shRNA-mediated SIX2 or SIX3 suppression in human pancreatic adult islets impairs insulin secretion. However, transcriptome studies revealed that SIX2 and SIX3 regulate distinct targets. Loss of SIX2 markedly impaired expression of genes governing β-cell insulin processing and output, glucose sensing, and electrophysiology, while SIX3 loss led to inappropriate expression of genes normally expressed in fetal β cells, adult α cells, and other non-β cells. Chromatin accessibility studies identified genes directly regulated by SIX2. Moreover, β cells from diabetic humans with impaired insulin secretion also had reduced SIX2 transcript levels. Revealing how SIX2 and SIX3 govern functional maturation and maintain developmental fate in native human β cells should advance β-cell replacement and other therapeutic strategies for diabetes.

中文翻译：

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SIX2 和 SIX3 协调调节人胰腺 β 细胞的功能成熟度和命运

许多重要组织和器官的生理功能在出生后继续成熟，但控制这种出生后成熟的遗传机制仍然是一个未解之谜。人类胰腺 β 细胞会根据葡萄糖等生理信号产生和分泌胰岛素，这些标志性功能会在出生后数年内得到改善。这与转录因子 SIX2 和 SIX3 的表达一致，它们在天然人类 β 细胞中的功能仍然未知。在这里，我们表明 shRNA 介导的SIX2或SIX3抑制人类胰腺成人胰岛会损害胰岛素分泌。然而，转录组研究表明SIX2和SIX3调节不同的目标。SIX2的损失控制 β 细胞胰岛素加工和输出、葡萄糖传感和电生理学的基因表达显着受损，而SIX3缺失导致通常在胎儿 β 细胞、成人 α 细胞和其他非 β 细胞中表达的基因表达不当。染色质可及性研究确定了受 SIX2 直接调控的基因。此外，来自胰岛素分泌受损的糖尿病人的 β 细胞也具有降低的SIX2转录物水平。揭示SIX2和SIX3如何控制功能成熟和维持天然人类 β 细胞的发育命运应该会促进 β 细胞替代和其他糖尿病治疗策略。