Abstract
The mammalian Caudal-related homeobox transcription factor 2 (CDX2) plays a key role in the homeobox regulatory network and is essential in regulating the expression of several homeobox (HOX) genes during embryonic development, particularly in the gut. Genome-wide CDX2 chromatin immunoprecipitation analysis and expression data from Caco2 cells also suggests a role for CDX2 in the regulation of HOXB4 gene expression in the intestinal epithelium. Thus, the aim of this study was to investigate whether HOXB4 gene expression is regulated by CDX2 in the intestinal epithelium. We demonstrated binding of CDX2 to four different CDX2 binding sites in an enhancer region located upstream of the HOXB4 transcription start site. Mutations in the CDX2 binding sites reduced HOXB4 gene activity, and knock down of endogenous CDX2 expression by shRNA reduced HOXB4 gene expression. This is the first report demonstrating the CDX2 regulation of HOXB4 gene expression in the developed intestinal epithelium, indicating a possible role for HOXB4 in intestinal homeostasis.
Highlights
Homeobox (HOX) proteins are important regulators during development and the formation of the anterior and posterior body plane in vertebrates
The regulation of HOXB4 expression is poorly understood in the intestinal epithelium and, until now, no other transcription factors in the intestinal epithelium have been shown to directly induce HOXB4 expression
We demonstrate that Caudal-related homeobox transcription factor 2 (CDX2) regulates HOXB4 gene expression in the intestinal epithelium-derived cell line SW480
Summary
Homeobox (HOX) proteins are important regulators during development and the formation of the anterior and posterior body plane in vertebrates. The 39 different HOX genes in humans can be divided into four different clusters, HOXA, HOXB, HOXC and HOXD, which are located on different chromosomes[1]. HOX genes are transcription factors belonging to the HOX protein family that share a DNA-binding domain, termed the HOX domain. The HOX domain is comprised of 60 amino acids that bind DNA in a sequence-dependent manner[2]. HOX gene expression is organ-specific, and the deregulation of specific HOX genes has been associated with cancer development[3]; these genes include HOXA9, which has been implicated in the development of acute myeloid leukemia[4], HOXD3, which increases invasiveness and metastasis in lung cancer[5], and both HOXA4 and HOXD10, which are overexpressed in colorectal cancer[6]
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