Abstract
The type II membrane-anchored serine protease, matriptase, encoded by suppression of tumorgenicity-14 (ST14) regulates the integrity of the intestinal epithelial barrier in concert with its inhibitor, HAI-1 encoded by serine peptidase inhibitor, Kunitz type -1 (SPINT1). The balance of the protease/inhibitor gene expression ratio is vital in preventing the oncogenic potential of matriptase. The intestinal cell lineage is regulated by a transcriptional regulatory network where the tumor suppressor, Caudal homeobox 2 (CDX2) is considered to be an intestinal master transcription factor. In this study, we show that CDX2 has a dual function in regulating both ST14 and SPINT1, gene expression in intestinal cells. We find that CDX2 is not required for the basal ST14 and SPINT1 gene expression; however changes in CDX2 expression affects the ST14/SPINT1 mRNA ratio. Exploring CDX2 ChIP-seq data from intestinal cell lines, we identified genomic CDX2-enriched enhancer elements for both ST14 and SPINT1, which regulate their corresponding gene promoter activity. We show that CDX2 displays both repressive and enhancing regulatory abilities in a cell specific manner. Together, these data reveal new insight into transcriptional mechanisms controlling the intestinal matriptase/inhibitor balance.
Highlights
The intestinal epithelium represents one of the most significant permeability barriers for exposure to environmental toxins and microorganisms[1]
The analyses showed that loss of Caudal homeobox 2 (CDX2) (- Dox) did not have an impact on either suppression of tumorgenicity-14 (ST14) or SPINT1 mRNA expression, as compared to wild-type LS174T cells, suggesting that their basal gene expression is not maintained by CDX2, showing CDX2 independence (Fig. 1)
Matriptase and SPINT1 are normally expressed in the epithelium of both small intestine and colon where they are involved in epithelial barrier integrity and are suggested to be involved in cellular turnover of the gut[3,39,40,41]
Summary
CDX2 stimulates ST14 gene expression while repressing SPINT1 gene expression in intestinal epithelial cells. The Caco-2 ChIP-seq tracks revealed that these distinct CDX2-binding peak regions were covered by H3K4me[2] marks (Figure S1 and S2), suggesting that these genomic sites have an open chromatin structure, making them possible active cis-regulatory enhancer elements in intestinal cells. These CDX2-bound regions within the ST14 and SPINT1 genomic locus were chosen to be characterized and investigated for their potential role of being enhancers for the gene promoters in intestinal cells.
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