Cartography and mechanism of enhanced transcriptome plasticity by transposable elements
Transposable elements (TEs) in our genome are the heritage of ancient parasitic infections. While most of human DNA is comprised of TEs and TE-derived elements, their repetitive nature poses technical challenges and thus little is known about their positional identity and regulatory roles. Here, by integrating long-read and multidimensional transcriptional analyses, we investigated when, where and how TEs become part of a gene. We characterized how TE-derived isoform and new genes change across mouse-human variation and are linked to gene regulatory networks controlling cell states during differentiation, organogenesis and health (aging and pathological states). Mechanistically, we identified an RNA degradation-dependent and a splicing-dependent quality control mechanism that operate independently of conventional mechanisms of TE suppression (DNA methylation and heterochromatinization) and prevents TE-exonization and TE-induced cell differentiation. Overall, our findings reveal new mechanisms by which viral-derived elements enhance transcriptome plasticity. Overall design: RNA-seq profiling of WT and Exosc3 cKO mESCs treated with major and minor splicing inhibitors (U1 and U6atac AMO) and MERVL ASO.