title: Glis3 regulates neurogenin 3 expression in pancreatic β-cells and interacts with its activator, Hnf6.
abstract: 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.
authors: Department of Microbiology, College of Medicine, Soonchunhyang University, Cheonan 314-864, Korea. yongsikkim@sch.ac.kr
authors: Yong-Sik
authors: YS
authors: Kim
authors: Hong Soon
authors: HS
authors: Kang
authors: Yukimasa
authors: Y
authors: Takeda
authors: Lisa
authors: L
authors: Hom
authors: Ho-Yeon
authors: HY
authors: Song
authors: Jan
authors: J
authors: Jensen
authors: Anton M
authors: AM
authors: Jetten
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D057809:HEK293 Cells; D056945:Hep G2 Cells; D051559:Hepatocyte Nuclear Factor 6 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D051559:Hepatocyte Nuclear Factor 6; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; C478000:Glis3 protein, mouse; C407737:Neurog3 protein, mouse