Cooperation between epitranscriptomics and the piRNA pathway in maternal mRNA regulation

• Applicant: Professor Dr. Jean-Yves Roignant
• Subject Area: Developmental Biology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 431556720

mRNA regulation is essential in a wide range of biological and pathological processes. This regulation involves RNA binding proteins and non-coding RNAs that act in a complex coordinated manner to determine the fate and function of cellular mRNAs. Piwi-interacting RNAs (piRNAs) are a specific class of small non-coding RNAs involved in the repression of transposable elements in the germline. Besides this well studied function, we have previously described a novel role for piRNAs in controlling maternal mRNA decay during early embryogenesis in the Drosophila model. Recently, mRNA modification, in particular N6-methyladenosine (m6A), has emerged as a novel critical layer of post-transcriptional gene regulation affecting every step of mRNA biogenesis, including the regulation of maternal mRNA decay in fish and mouse. Yet, it is unknown whether and how the piRNA and m6A pathways may coordinate to ensure efficient maternal mRNA degradation. Our preliminary data indicate that m6A contributes to the decay of the well-studied nanos maternal mRNA in early Drosophila embryo, suggesting that this m6A function is conserved in flies. In addition, we have found that a proportion of m6A sites lie near piRNA binding sites on maternal mRNAs, suggesting the possibility that m6A might participate in the specificity of mRNA recognition by piRNAs. Based on our preliminary work, the objective of the m6ApiRNA project is to decipher the crosstalk between the piRNA pathway and RNA modification during the early steps of animal development. We will investigate the interplay between m6A, the most abundant modification on mRNA, and the piRNA pathway in two critical events that are required during early Drosophila embryogenesis for embryonic patterning: 1) maternal mRNA decay in the soma and 2) the localization of germ plasm mRNAs at the posterior pole of the embryo and their translational activation. The specific work packages include: i) the use of genomic, imaging and CRISPR/Cas9-mediated approaches to examine the contribution of m6A in maternal mRNA decay; ii) the identification of mRNAs co-regulated by m6A and piRNAs, and the underlying mechanisms and iii) the interplay between m6A and piRNAs in maternal mRNA localization and translational activation. This collaborative study will combine cutting-edge Drosophila genetics, ribonomics and imaging approaches, molecular biology and mass spectrometry to address the relationships between m6A and the piRNA pathway in the regulation of maternal mRNAs during early embryogenesis. Deciphering the cooperation between these two modes of regulation will have a strong impact in the emerging fields of piRNA biology and epitranscriptomics in mRNA regulation.

• DFG Programme: Research Grants
• International Connection: France
• Cooperation Partner: Dr. Martine Simonelig, Ph.D.