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.Morphogenesis of the digestive tract is the result of several steps through development beginning with gross morphogenesis of the organ and then cytodifferentiation of the epithelium and induction of intestine-specific genes in the establishment of the functional adult epithelium (40). In the mouse small intestine, cytodifferentiation occurs between embryonic days 14 and 15 with the transition from a stratified epithelium to a columnar epithelium with nascent villi. Small intestine villi lengthen and crypts form through the first two postnatal weeks. The early development of the mouse colon shows transient similarities to that of the small intestine, with the formation of villus structures. This temporary colonic architecture regresses early during development to form the adult colonic mucosa (39). Early developmental similarities between the small intestine and colon in humans have also been described (21).The sucrase-isomaltase (SI) gene represents a useful model to elucidate the mechanisms of intestinal development. This gene encodes an enzyme that is expressed in the brush border of mature enterocytes in a complex developmental pattern (19,20,42). A low level of SI gene expression is first detectable in the mouse embryonic intestine, and this expression remains stable through the first 2 weeks of life after birth. A similar low and transient level of expression is also detected in the colon during early postnatal life (42). Between days 16 and 17, there is a dramatic induction of SI expression in enterocytes located at the crypt-villus junction in the small intestine (42). Similar transient expression of SI, as well as other intestinal brush border enzymes, has also been observed in the human fetal colon (48). It has been suggested that the mechanisms directing transient SI expression in the colon are recapitulated in the process of human colonic neoplasia, with the reexpression of SI in the majority of colonic adenomatous polyps and adenocarcinomas (4, 9, 45). A comparable recurrence of SI expression was also found in rodent colon tissues subjected to oncogene-mediated transformations (29). Therefore, the delineation of...

Polycomb repressive complex 2 impedes intestinal cell terminal differentiation

“…Indeed, besides the previously reported inhibitory mechanisms of intestinal cell differentiation (Houde et al, 2001;Rings et al, 2001;Boudreau et al, 2002a;Tou et al, 2004;Mariadason, 2008;Verzi et al, 2010) detailed above, our studies using the two distinct intestinal cells models Caco-2/15 and HIEC CDX2/HNF-1a showed that the activity of the PRC2 component of PcG specifically repressed the expression of a number of terminal differentiation markers. In situ, the cornerstone PRC2 component SUZ12 was identified in a significant proportion of colon tumours and found predominantly in the TA zone in the normal small intestine suggesting that PcG proteins may also participate in the repressive mechanism of terminal differentiation in vivo.…”

“…Because the main pro-differentiation transcription factors are expressed in these cells, one may consider various mechanisms known to negatively modulate their transcriptional activity such as post-translational modifications (Houde et al, 2001;Rings et al, 2001), expression of transcriptional repressors (Boudreau et al, 2002a) and/or epigenetic mechanisms such as histone modifications (Tou et al, 2004;Mariadason, 2008;Verzi et al, 2010). Another possibility not yet investigated could be epigenetic control of gene expression via polycomb group (PcG) proteins.…”

Functional Characterization of the CCL25 Promoter in Small Intestinal Epithelial Cells Suggests a Regulatory Role for Caudal-Related Homeobox (Cdx) Transcription Factors

“…‫,ء‬ p Ͻ 0.05; ‫,ءء‬ p Ͻ 0.01. small intestine vs colon are poorly understood. For the small intestinal specific gene sucrase isomaltase, tissue selectivity is achieved through the combination of HNF-1␣, GATA-4, and Cdx-2 (48), together with active suppression of this gene in the colon (57). Promoter analysis using MatInspector predicted a binding site for this repressor (CLOX/CDP) within the CCL25 promoter.…”

CDX2 : un facteur à multiples facettes pour les cellules épithéliales du tube digestif

“…De nombreuses pathologies de l'épithélium intestinal, en l'occurrence le cancer colorectal, découlent directement du dérègle-ment des mécanismes régissant cet équilibre. L'utilisation de modèles cellulaires et de souris transgéniques a montré l'importance positionnelle et combinatoire de certains facteurs de transcription dans la régulation de marqueurs associés à la différencia-tion épithéliale tout le long du tube digestif [1,2]. CDX2, un facteur de transcription exprimé spécifiquement dans l'épithélium intestinal, repré-sente un candidat important dans la mise en oeuvre d'un programme spécifique de différenciation temporelle en fonction des segments de l'épithélium du tube digestif.…”