Department of Microbiology, College of Medicine, Soonchunhyang University, Cheonan 314-864, Korea.
Mol Cells. 2012 Aug;34(2):193-200. doi: 10.1007/s10059-012-0109-z. Epub 2012 Jul 20.
The Krüppel-like zinc finger transcription factor, Glis3, has been associated with neonatal diabetes in humans and mice, and implicated in the regulation of pancreatic β-cell generation. However, its precise function in the development of pancreatic β-cells has not yet been elucidated. In this study, we provide evidence that Glis3 regulates Neurogenin 3 (Ngn3) through its distal promoter region. Previous studies showed that the distal region and proximal region of Ngn3 promoter contains various transcription binding sites, including binding sites for pancreatic and duodenal homeobox 1 (Pdx1), Hnf1β and Hnf6. Interestingly, putative Glis3 binding sites (Glis3BS) were found in the distal region of Ngn3 promoter close to the Hnf6 binding sites. This suggested that along with Hnf6, Glis3 may also be involved in the regulation of Ngn3 expression. This hypothesis is supported by data showing that Glis3 can bind to the Ngn3 promoter directly and activate Ngn3 transcriptional activity. Additionally, Glis3 can interact directly with Hnf6 in vitro and in vivo. The amino-terminus in Glis3 and the homeodomain of Hnf6 are critical for this interaction. These data suggest that crosstalk between Glis3 and Hnf6 may play an important role in the regulation of Ngn3 during pancreatic endocrine progenitor cell specification and development.
Krüppel 样锌指转录因子 Glis3 与人类和小鼠的新生儿糖尿病有关，并与胰腺 β 细胞生成的调节有关。然而，其在胰腺 β 细胞发育中的精确功能尚未阐明。在这项研究中，我们提供了证据表明 Glis3 通过其远端启动子区域调节神经基因 3（Ngn3）。先前的研究表明，Ngn3 启动子的远端区域和近端区域包含各种转录结合位点，包括胰腺和十二指肠同源盒 1（Pdx1）、Hnf1β 和 Hnf6 的结合位点。有趣的是，在 Ngn3 启动子的远端区域靠近 Hnf6 结合位点处发现了假定的 Glis3 结合位点（Glis3BS）。这表明，与 Hnf6 一起，Glis3 也可能参与 Ngn3 表达的调节。这一假设得到了以下数据的支持：Glis3 可以直接结合到 Ngn3 启动子上并激活 Ngn3 的转录活性。此外，Glis3 可以在体外和体内直接与 Hnf6 相互作用。Glis3 的氨基末端和 Hnf6 的同源域对于这种相互作用至关重要。这些数据表明，Glis3 和 Hnf6 之间的串扰可能在胰腺内分泌祖细胞特化和发育过程中调节 Ngn3 表达中发挥重要作用。
