Liver-specific Mettl14 deletion induces nuclear heterotypia and dysregulates RNA export machinery

Abstract

AbstractModification of RNA with N6-methyladenosine (m6A) has gained attention in recent years as a general mechanism of gene regulation. In the liver, m6A, along with its associated machinery, has been studied as a potential biomarker of disease and cancer, with impacts on metabolism, cell cycle regulation, and pro-cancer state signaling. However these observational data have yet to be causally examinedin vivo.For example, neither perturbation of the key m6A writersMettl3andMettl14, nor the m6A readersYthdf1andYthdf2have been thoroughly mechanistically characterizedin vivoas they have beenin vitro. To understand the functions of these machineries, we developed mouse models and found that deletingMettl14led to progressive liver injury characterized by nuclear heterotypia, with changes in mRNA splicing, processing and export leading to increases in mRNA surveillance and recycling.