The role of N6-methyladenosine in translational control of the immune response

• Applicant: Dr. Jan Mauer
• Subject Area: Immunology ; Biochemistry ; Cell Biology
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 280429966

The Jaffrey Laboratory recently published a landmark study in which they showed for the first time that N6-methyladenosine (m6A) is a widespread, reversible base modification in mRNA. m6A exhibits a unique distribution within mRNAs, with the most highly enriched regions being near the stop codon and in the 5-prime UTR. According to preliminary data from the Jaffrey group, localization of m6A in specific regions of a transcript can influence mRNA fate. Intriguingly, m6A is particularly abundant in immune cells and its levels and localization within mRNAs can be dynamically regulated by inflammatory stimuli. This suggests that mRNA methylation is a widespread mechanism of mRNA regulation in the immune system, which contributes to shaping inflammatory responses. However, despite the prevalence of m6A within immune cells and its potential to influence a substantial portion of the inflammation-associated transcriptome, its function remains largely unknown. The research plan proposed here will utilize a combination of technically and conceptually innovative approaches to investigate the localization, regulation and function of m6A in mRNAs. In Aim 1, I will first identify the mRNAs that are dynamically methylated during the inflammatory response in macrophages. I will then utilize a combination of biochemical experiments and m6A mapping techniques together with next-generation sequencing approaches to define the mechanism that controls m6A localization in mRNAs of macrophages. These experiments will help answer the long-standing question of how adenosine methylation is directed to particular regions of a transcript. In Aim 2, I will explore the role of m6A in regulating mRNA translation in macrophages. The results of these experiments will provide important insight into how m6A contributes to basic immune cell function and will propel our understanding of the molecular and epigenetic events that contribute to immune responses in health and disease.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Samie R. Jaffrey, Ph.D.