Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
Department of Medicine (Endocrinology), Stanford University School of Medicine, Stanford, California 94305, USA.
Genes Dev. 2021 Feb 1;35(3-4):234-249. doi: 10.1101/gad.342378.120. Epub 2021 Jan 14.
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 or suppression in human pancreatic adult islets impairs insulin secretion. However, transcriptome studies revealed that and regulate distinct targets. Loss of markedly impaired expression of genes governing β-cell insulin processing and output, glucose sensing, and electrophysiology, while 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 transcript levels. Revealing how and govern functional maturation and maintain developmental fate in native human β cells should advance β-cell replacement and other therapeutic strategies for diabetes.
许多重要组织和器官的生理功能在出生后仍继续成熟，但控制这种出生后成熟的遗传机制仍是一个未解之谜。人类胰腺β细胞在受到葡萄糖等生理信号刺激时会产生和分泌胰岛素，这些标志性功能在出生后数年中会得到改善。这与转录因子 SIX2 和 SIX3 的表达相吻合，但其在天然人β细胞中的功能仍不清楚。在这里，我们表明，在人胰腺成年胰岛中通过 shRNA 介导的 或 抑制会损害胰岛素分泌。然而，转录组研究表明 和 调节不同的靶标。 的缺失显著损害了调节β细胞胰岛素加工和输出、葡萄糖感应和电生理学的基因的表达，而 的缺失导致通常在胎儿β细胞、成年α细胞和其他非β细胞中表达的基因的异常表达。染色质可及性研究鉴定了由 SIX2 直接调控的基因。此外，胰岛素分泌受损的糖尿病人类β细胞中的 转录本水平也降低了。揭示 和 如何在天然人β细胞中调控功能成熟并维持发育命运，应该会推进β细胞替代和其他糖尿病治疗策略。
