A Novel Colonic Repressor Element Regulates Intestinal Gene Expression by Interacting with Cux/CDP

Abstract

Intestinal gene regulation involves mechanisms that direct temporal expression along the vertical and horizontal axes of the alimentary tract. Sucrase-isomaltase (SI), the product of an enterocyte-specific gene, exhibits a complex pattern of expression. Generation of transgenic mice with a mutated SI transgene showed involvement of an overlapping CDP (CCAAT displacement protein)-GATA element in colonic repression of SI throughout postnatal intestinal development. We define this element as CRESIP (colon-repressive element of the SI promoter). Cux/CDP interacts with SI and represses SI promoter activity in a CRESIP-dependent manner. Cux/CDP homozygous mutant mice displayed increased expression of SI mRNA during early postnatal development. Our results demonstrate that an intestinal gene can be repressed in the distal gut and identify Cux/CDP as a regulator of this repression during development.

We thank J.-F. Brunet for providing the pRcCMV/Cux vector, E. J. Neufeld for the CDP antibody, and M. S. Parmacek for providing the GATA-4, -5, and -6 expression vectors. We also thank Sandy Mancano and João Pedro Teixeira for technical assistance.

This work was supported by RO1-DK47437 and RO1-DK46704 (to P.G.T.), RO1-GM50329 (to R.H.S.) and the Transgenic, Morphology and Molecular Biology Cores of the Center for Molecular Studies in Digestive and Liver Diseases at the University of Pennsylvania (P30-DK50306). F.B. was supported by a postdoctoral fellowship from the Fonds de la Recherche en Santé du Québec. E.H.H.M.R. was recipient of a grant from Ter Meulen Fund, Royal Netherlands Academy of Arts and Sciences, The Netherlands, of a TALENT-stipendium from The Netherlands Organization for Scientific Research (NW), The Netherlands, and of an International Training Fellowship from the Nutricia Research Foundation, The Netherlands.