TE-DRIVER · Investigating the causal effects of transposable elements on downstream transcription within genomic context

Transposable elements (TEs) make up about half of both the human and mouse genomes, playing a crucial role in genome plasticity and evolution. Most TEs have accumulated mutations that disable their transposition, but even fragmented TEs are often co-opted by the host into complex regulatory systems like promoters, enhancers and silencers, profoundly influencing gene and chromatin regulation. For example, a retrotransposon acts as a promoter to drive the expression of a specific isoform of Cdk2ap1, which is crucial for pre-implantation development. However, TEs can also trigger senescence and oncogene expression, making them a ""double-edged sword"" in biology. Given TEs’s dual role, the activity and regulation of TEs driving downstream transcription is extremely important for cellular homeostasis. Studies have suggested a potential role for TEs as promoters, yet evidence is fragmentary and indirect. The sufficiency of TEs in autonomously driving transcription, their interaction with genomic context, and differences between TEs in various genomic context remain largely unknown. The TE-Driver project aims to systematically and directly investigate TEs transcriptional activity and its regulation by genomic context such as DNA methylation, histone modifications and chromatin structure. TE-Driver will integrate representative TEs (MT2_Mm, L1MdTf_II, and B3A) into thousands of genomic locations in mouse embryonic stem cells (mESCs). TE integration sites will be captured via inverse PCR coupled with high-throughput sequencing, and transcriptome changes will be analyzed using Smart-seq+5’. The project will integrate these datasets with publicly available datasets on genomic context to evaluate TEs sufficiency in driving transcription within genomic contexts and elucidate differences among TEs. TE-Driver aims to advance our understanding of TE mechanisms in genome regulation and contribute to fields such as stem cell biology, developmental biology and functional genomics.""