CTCF-regulating endocrine function of pancreatic islet cells in transgenic mice.

Abstract

Pancreatic islet endocrine cells play crucial roles in regulation of glucose homeostasis. The differentiation and function of islet cells are regulated by various transcription factors, including Pax6, a member of the homeobox gene family. Pax6 plays a key role in the control of gene expression and islet cell development in the pancreas. Recent studies from our lab demonstrate for the first time that Pax6 transcription is regulated by CCCTC binding factor (CTCF), a nuclear protein and transcription regulator. CTCF downregulates Pax6 transcription through interaction with a repressor element located in Pax6 gene P0 promoter region. To further investigate the effect of CTCF on regulating Pax6 function in pancreatic islet cells, we measured blood glucose, insulin, and glucagons levels in newly established transgenic mice overexpressing CTCF. When compared to wild type mice, CTCF transgenic mice demonstrate an increase in insulin level and decrease in glucagon level resulting in lower blood glucose levels (hypoglycemia). In insulin tolerance test, hypoglycemia occurs quickly in CTCF transgenic mice and takes a recovery time. In the mean time, glucagon levels in CTCF mutant mice were significantly lower compared to its wild type counterpart. Our results indicate that CTCF transgenic mice are disordered in glucose homeostasis and suggest that CTCF is involved in regulating endocrine function of pancreatic islet cells by suppression of Pax6 expression.