Protein arginine methyltransferase 1 regulates adult intestinal epithelial cell proliferation and differentiation

FARE Award Winner

Authors

• CL Shults
• R Aminapour
• B Milon
• K Gwilliam
• E Chrysostomou
• MR Bowl
• R Hertzano

Abstract

The adult intestinal epithelium is a complex, self-renewing tissue composed of specialized cell types with diverse functions. Intestinal stem cells (ISCs) at the base of crypts divide and differentiate into absorptive and secretory cells. Enteroendocrine cells (EEC), one type of secretory cells, are the most abundant hormone-producing cells in mammals and involved in the control of energy homeostasis. Many studies investigated the mechanisms that control cell fate determination; however, regulation of EEC development and function is still unclear.
Here, we found that Protein arginine methyltransferase 1(PRMT1) is highly expressed in the proliferating transit-amplifying (TA) cells and ISCs of adult mouse intestinal crypts. By using tamoxifen-induced intestinal epithelial cell-specific deletion of PRMT1 in adult mice, we observed the number of EEC dramatically increased. Transcription analyses showed all top enriched upregulated pathways of PRMT1-deficient small intestine were associated with EEC functions and gene expression of Enteroendocrine-specific hormone and transcription factors were upregulated. Concomitantly, Neurogenin 3-expressing progenitor cells accumulated in the mutant small intestine. Furthermore, mutant mice showed elongated crypts in the small intestine, while increased cell proliferation in TA cells. Additionally, inducible PRMT1 deletion led to increased cell death, which compensated for increased cell proliferation in the crypts to maintain overall intestinal morphology and intestinal homeostasis.
Together, our results revealed that the loss of PRMT1 in the adult intestinal epithelium altered TA cell proliferation and EEC differentiation, which probably via enhancement of Neurogenin 3-mediated commitment to the EEC lineage.

Scientific Focus Area: Cell Biology

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