PRC1 (polycomb complex) maintains intestinal homeostasis by repressing the expression of ZICs, a family of transcription factors inactivating the β-catenin/TCF complex. Importantly, interfering with PRC1 activity completely inhibits the formation of Wnt-dependent tumors.
Researchers at the University of Tampere discovered a regulation mechanism governing the intestinal homeostasis. Disturbances in this mechanism are implicated in celiac disease and possibly also in colorectal cancer. The study provides new information on the pathogenesis of the differentiation defect of the epithelium in the small intestine in celiac disease.
In celiac disease, ingested dietary gluten causes intestinal mucosal damage with villus atrophy and crypt hyperplasia. At the cellular level, epithelial cells are less differentiated and hyper-proliferative leading to the malabsorption of nutrients. Researchers discovered that a certain epigenetic mechanism (Polycomb) governs the homeostasis between the intestinal stem cells in the crypt and the differentiated epithelium in the villi. Polycomb is silencing the genes epigenetically by methylating histone proteins that are packing the DNA.
“Polycomb is well-known for its function to regulate embryonal development. We discovered that Polycomb is also able to regulate the homeostasis of the small intestine in adults. The regulation of intestinal homeostasis is a tremendous task as the epithelium of the intestine needs to be replenished completely every 4-5 days,” says Academy of Finland Postdoctoral Researcher and Principal Investigator Keijo Viiri.
In celiac disease, dietary gluten induces excessive activity of Polycomb leading to the aberrant silencing of genes necessary for the differentiation of villus epithelium and to the concomitant differentiation defect in celiac disease. In addition, the study shows Polycomb target genes are dysregulated also in colorectal cancer, suggesting that aberrant Polycomb activity is a common attribute in intestinal diseases entailing a differentiation defect on the intestinal epithelium.
From a clinical point of view, this work sheds light on the pathogenesis of the intestinal damage in celiac disease and provides diagnostic markers for the disease. As Polycomb regulates only genes imperative for development, this work is also instrumental to further understand the biology of the intestinal homeostasis. The study was performed by PhD Keijo Viiri’s research group at the University of Tampere. http://www.alphagalileo.org/ViewItem.aspx?ItemId=167581&CultureCode=en
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