Effect of Uhrf1 on intestinal development.

As a best-characterized epigenetic modification, DNA methylation plays an important role in mammalian development. Uhrf1 is a critical epigenetic regulator that can bind to hemimethylated DNA and recruit DNA methyltransferase 1 to maintain DNA methylation. So far, the role of Uhrf1-mediated DNA methylation in intestinal development is still unknown. In order to investigate the impact of Uhrf1 deletion in intestinal development, we have successfully constructed the epithelial-specific Uhrf1 knockout mouse model. After Uhrf1 ablation, we found the mutant mice exhibited abnormal epithlial structure with less and shorter villi and shrinked crypts compared with wild type mice via hematoxylin-eosin staining. Further analysis showed that Uhrf1 deletion in the intestinal epithelium significantly decreased the cell proliferation and induced cell apoptosis. In addition, Uhrf1 deletion inhibited the normal epithelial differentiation and the expression of intestinal stem cell marker genes. Preliminary mechanism study revealed that loss of Uhrf1 caused global DNA hypomethylation which induced DNA damage in crypt cells. Taken together, our data suggested that DNA methylation mediated by Uhrf1 is vital for the normal intestinal development. Our results enriched the in vivo role of Uhrf1 and laid the foundation for further epigenetic regulatory mechanism exploration.