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The role of m6A RNA modifications in the evolution of gene regulation

Supervisor: Julian König

Co-Supervisor: Susanne Foitzik, Claudia Keller Valsecchi


Scientific Background:
Posttranscriptional regulation of RNA is critical for the control of gene expression in cellular differentiation and animal development. RNA modifications play an important role in the regulation of RNA and this expanding research field has been termed epitranscriptomics. N6-methyladenosine (m6A) is the most abundant modification in mRNA. m6A is co-transcriptionally deposited in the nucleus by the METTL3 writer complex and has been shown to regulate several aspects of RNA function, most prominently RNA stability. Hence, this epitranscriptomic mark inherits information from the nucleus to impact on the regulation of RNA in the cytoplasm. To map m6A modifications in a transcriptome-wide manner, we recently developed the miCLIP2 approach, which combines improved next-generation library preparation with machine learning [1]. This approach will be our central tool to learn about the role of m6A in the two projects below on the role of m6A in vertebrate gene expression and caste development.


PhD project: The role of m6A RNA modifications in the evolution of gene regulation

Project part A: The role of m6A in vertebrate gene expression. In this project, we aim to understand the role of m6A in gene regulation in different mammalian and vertebrate species. For this project we will combine our expertise in functional genomics (iCLIP, miCLIP, High-throughput sequencing approaches), molecular biology and computational approaches, to dissect how the m6A machinery is positioned on transcripts in different mammalian and vertebrate species. We will characterize the intrinsic specificity of the core enzyme METTL3 and how it is guided by auxiliary RNA binding proteins or modulated by secondary structure. This will help us to understand how these epigenetic marks are placed on the nascent RNAs to determine their fate in the cytoplasm.

Project part B: The role of m6A in caste development in ants. Caste differentiation in ants and other social insects relies on gene-regulatory mechanisms since both workers and queens share the same genetic material. Recently, it was shown that m6A RNA modifications play a crucial role in caste differentiation in the honeybee. Transcripts are hypermethylated in workers, and inhibition of m6A methylation results in workers with queen caste features. In this part of the project, we will investigate the role of m6A in ant caste differentiation. To this end, we will generate transcriptome-wide maps of m6A methylation in workers and queens to learn which genes exhibit differential methylation. For comparison, we will also include male ants which are only haploid and might require “dosage compensation” for all chromosomes.


Publications relevant to this project
Körtel N, Rückle C, Zhou Y, Busch A, Hoch-Kraft P, Sutandy FXR, Haase J, Pradhan M, Musheev M, Ostareck D, Ostareck-Lederer A, Dieterich C,  Huttelmaier S, Niehrs C, Rausch O, Dominissini D, König J & Zarnack K. Deep and accurate detection of m6A RNA modifications using miCLIP2 and m6Aboost machine learning. Nucleic Acids Res 49, e92 (2021).