The role of piRNAs and N6-methyladenosine (m6A) in the epidermis of planarians

• Applicant: Professor Dr. Claus-Dieter Kuhn, Ph.D.
• Subject Area: General Genetics and Functional Genome Biology ; Biochemistry ; Developmental Biology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 450313021

Planarian flatworms are an excellent model system to study the genetic and molecular foundation of regeneration. Their marvelous regenerative abilities are fueled by an abundant population of cells called neoblasts, pluri- and multipotent stem cells that are capable of replenishing any missing cell type in adult worms. For proper function, neoblasts must communicate with the differentiated cells that surround them, which includes receiving developmental cues from those cells to launch a proper regenerative response. Previously, we characterized the planarian piRNA pathway in neoblasts and differentiated cells. piRNAs are small, animal-specific, regulatory RNAs that bind to PIWI proteins and that were found essential for planarian regeneration. Our work revealed that, in planarians, piRNAs not only counteract transposable elements post-transcriptionally and epigenetically, but they are also intimately linked to mRNA surveillance, potentially taking over part of the function that microRNAs fulfill in other animals. In addition, we discovered a somatic piRNA pathway in the planarian epidermis that operates with the use of a single PIWI protein. This is an intriguing finding, as the epidermis is composed of terminally differentiated cells and exhibits rapid tissue turnover. Hence, it does not need to protect its genome from transposable elements. Based on preliminary analyses and on the fact that the epidermis is the first barrier to pathogens, we hypothesize that the epidermal piRNA pathway serves innate immune functions in planarians. With this proposal we therefore aim to characterize the epidermal piRNA pathway of planarians by applying both biochemistry and molecular biology in systems biology and single-cell approaches. In particular, we will dissect how epidermal cells decode exposure to pathogens into piRNA and transcriptomic changes and how this information is transmitted to other cells (especially neoblasts) in the planarian body. In the second part of this project, we aim to unravel the impact of m6A-modified mRNA on translation in epidermal cells. As our preliminary data suggests that the functional role of m6A differs fundamentally between the planarian epidermis and neoblasts, this investigation will provide important additional insight into the unique biological function and molecular mechanisms of the epidermis. In summary, our results will reveal how planarians utilize their epidermis to fight infection and other foreign invasions and how epidermal cells communicate such events to planarian stem cells. Moreover, this project will provide first insights into the role of m6A-modified mRNAs in planarians, especially regarding their epidermis-specific function. Finally, our results will make it possible to uncover connections between piRNAs and m6A modifications. In my view, such connections are likely because both mechanisms are involved in fine-tuning gene expression.

• DFG Programme: Research Grants