Epithelial m6A mRNA Methylation in Intestinal Morphogenesis.

Post-transcriptional modifications of mRNA have emerged as a central mechanism to control genetic information flow. N6-methyladenosine (m6A) is the most abundant post-transcriptional modification in eukaryotic mRNAs. It is known that m6A methylation directs mRNAs to distinct fates for differential processing, translation and decay in various biological processes; however, the role of m6A methylation in intestinal physiology is unknown. We have sought to understand the role of m6A methylation in intestinal biology by genetically deleting METTL14, a core subunit of m6A methyltransferase. Mice with METTL14 deletion in gut epithelial cells suffered severe growth retardation and high premature mortality with aberrant intestinal structure. The objective of this project is to understand how epithelial m6A methylation regulates intestinal development. We will assess the effect of gut epithelial METTL14 deletion on intestinal morphogenesis, epithelial cellular diversity and cell type distribution in mice, as well as on the formation and structure of gut epithelial organoids in culture. We will identify METTL14-targeted transcripts and pathways in each cell population that are involved in intestinal morphogenesis, particularly those involved in the control of intestinal stem cell self-renewal and differentiation. We will also assess the effect of METTL14 deletion on the structure and composition of gut luminal bacteria.