Widespread contribution of transposable elements to the rewiring of mammalian 3D genomes

Transposable elements (TEs) are major contributors of genetic material in mammalian genomes. These often include binding sites for architectural proteins, including the multifarious master protein, CTCF, which shapes the 3D genome by creating loops, domains, compartment borders and RNA-DNA interactions, all of which play a role in the compact packaging of DNA and have the potential to facilitate regulatory function. In this study, we explore the widespread contribution of TEs to mammalian 3D genomes by quantifying the extent to which they give rise to loops and domain border differences across various cell types and species using several 3D genome mapping technologies. We show that specific (sub-)families of TEs have contributed to lineage-specific 3D chromatin structures across mammalian species. In many cases, these loops may facilitate interaction between distant cis-regulatory elements and target genes, and domains may segregate chromatin state to impact gene expression in a lineage-specific manner. An experimental validation of our analytical findings using CRISPR-Cas9 to delete a candidate TE resulted in disruption of species-specific 3D chromatin structure. Taken together, we comprehensively quantify and selectively validate our finding that TEs contribute to 3D genome organization and may, in some cases, impact gene regulation during the course of mammalian evolution. Overall design: HiC^2, (chr7:157.1-159.1MB), RNA-seq, and ATAC-seq on GM12878 WT and knockouts of region with L1MC1 loop anchor