Book Description

The intestinal epithelium absorbs nutrients and forms a barrier between luminal microorganisms and immune cells in the submucosa. Intestinal epithelial cells (IECs) are continuously replenished by intestinal stem cells, which generate both secretory and absorptive lineages of differentiated IECs. The expression of genes involved in IEC proliferation and differentiation must be precisely controlled to ensure epithelial barrier integrity and prevent malignancy. RNA-binding proteins fine-tune gene expression post-transcriptionally and have been implicated in the maintenance of IEC homeostasis. We investigated the role of RNA-binding protein, Tristetraprolin (TTP), encoded by the Zfp36 gene, in IEC homeostasis and disease. TTP binds to AU-rich elements in the 3UTR of a subset of mRNAs and targets them for degradation. Many established TTP target genes encode inflammatory modulators and proto-oncogenes, however it is unknown what genes are regulated by TTP in IECs. To elucidate a functional role for TTP in the intestinal epithelium, we generated IEC mice, which lack expression of Zfp36 in the IECs. We found that epithelial TTP is largely dispensable for intestinal homeostasis. However, the colons of IEC mice exhibit increased crypt depth and a mild expansion of the proliferative zone. Additionally, RNA-sequencing of colon tissue from control (Zfp36fl/fl) and IEC mice identified IEC-specific TTP target genes, including nitric oxide synthase 2 (Nos2), which, we demonstrate, is regulated by TTP through AU-rich elements in its 3UTR. Strikingly, upon DSS-induced colitis, IEC mice were protected from the pathologies associated with colitis, including weight loss, colon shortening, and perturbed colonic mucosal architecture. Additionally, IEC mice had enhanced tumor growth in AOM-DSS induced colitis-associated cancer. These findings uncover roles for TTP in IECs, including modulating Nos2 expression, regulating IEC regeneration, and suppressing tumor expansion.