The Role of Nuclear Organization and Chromatin Regulation in Solo LTR Silencing and their Genomic Stability

• Applicants: Professor Dr. Sigurd Braun; Dr. Cornelia Kilchert
• Subject Area: General Genetics and Functional Genome Biology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 578318831

Retrotransposons are mobile genetic elements of viral origin that are widespread across eukaryotic genomes. Their ability to integrate into diverse genomic sites can disrupt gene functions and compromise genome integrity, yet they are important drivers of genome evolution and structural diversity. To counteract these potentially harmful effects, cells have evolved multiple mechanisms to suppress retrotransposon expression and limit recombination. However, even after losing mobility, retrotransposon remnants such as solo long terminal repeats (LTRs) persist. These elements retain promoter- and enhancer-like properties that influence local gene expression and serve as substrates for recombination, posing a continuous threat to genome stability. Although the repression of full-length retrotransposons has been studied extensively, the mechanisms that govern solo LTR regulation remain poorly understood. This proposal addresses this gap using the fission yeast Schizosaccharomyces pombe, which provides powerful tools for dissecting chromatin regulation and nuclear organization. We hypothesize that the spatial positioning of solo LTRs relative to subnuclear domains is critical for controlling their transcriptional activity and recombinogenic potential. The proposed research focuses on two central regulators: the nuclear envelope protein Lem2 and the nucleosome remodeler Fft2. Prior work has shown that Lem2 coordinates multiple silencing pathways at the nuclear periphery, while Fft2 binds directly to LTRs. Importantly, Fft2 recruitment to Tf1- and Tf2-derived LTRs depends on Lem2 and its role in RNA degradation, whereas other LTRs are regulated independently by these factors. This suggests a multifaceted regulatory framework in which Lem2 and Fft2 act through both shared and distinct mechanisms. We will (i) define how Fft2’s RNA-binding activity and RNA-dependent processes contribute to solo LTR regulation; (ii) dissect how Lem2 interfaces with Fft2 and other silencing pathways, particularly under stress conditions; and (iii) determine how nuclear positioning of solo LTRs influences transcriptional repression and recombination frequency. By integrating genetic screens, functional genomics, biochemical approaches, and imaging, we will identify the mechanisms through which Lem2 and Fft2 regulate solo LTRs. This comprehensive analysis will establish a mechanistic framework for understanding how cells manage solo LTRs and restrict their recombinogenic activity. The findings will advance knowledge of chromatin regulation, nuclear organization, and genome stability, and may reveal conserved strategies for retrotransposon repression across eukaryotes.

• DFG Programme: Research Grants