Programmable Protein Expression Using a Genetically Encoded M6a Sensor

The N 6 -methyladenosine (m 6 A) modification is found in thousands of cellular mRNAs and is a critical regulator of gene expression and cellular physiology. m 6 A dysregulation contributes to several human diseases, and the m 6 A methyltransferase machinery has emerged as a promising therapeutic target. However, current methods for studying m 6 A require RNA isolation and do not provide a real-time readout of mRNA methylation in living cells. Here we present a g enetically encoded m 6 A sensor (GEMS) technology, which couples a fluorescent signal with cellular mRNA methylation. GEMS detects changes in m 6 A caused by pharmacological inhibition of the m 6 A methyltransferase, giving it potential utility for drug discovery efforts. Additionally, GEMS can be programmed to achieve m 6 A-dependent delivery of custom protein payloads in cells. Thus, GEMS is a versatile platform for m 6 A sensing that provides both a simple readout for m 6 A methylation and a system for m 6 A-coupled protein expression.