Role of transposable elements in gene regulation

Abstract

Transposable elements (TEs) have versatile roles in regulating genes of the host genome. TEs, by harboring intrinsic regulatory sequences and by emerging de novo regulatory elements through post insertion mutation events, provide a repertoire of cis regulatory elements in the host genome. In this thesis, we addressed TEs’ role in evolution of gene regulation within the primate lineage focusing on human and chimpanzee. The thesis comprises of three studies, each presented as a separate data chapter. In the first study we addressed the tissue-specificity of TE-mediated gene regulation by separately analyzing three different categories of regulatory region annotations from the ENCODE project using humans as a representative species. We inferred potential TE-regulated genes in 14 cell lines belonging to 10 different tissue types. We revealed a differential pattern of potential TE-regulated genes across cell lines, with relevance to the tissue-specific functionalities. In the second study, we examined the role of TEs in evolving TADs between human and chimpanzee using HiC data of two matching pairs of cell types. Our results support a multi-facet participation of TEs in the evolution of TADs, including emergence of species-specific TADs and stabilizing conserved TADs by providing CTCF binding site turnover at anchors both via species specific TEs (SSTEs), and formation of species-specific TADs via differentially co-opted TEs. In the third study, we particularly examined SSTEs’ impact on the species-specific up and downregulated genes between human and chimpanzee. We compiled lists of cases of species specific up and downregulated genes (harboring SSTEs with active and repressive marks respectively) with function in species-specific biological differences. Overall, the work in this thesis extends our knowledge for TEs’ contribution to gene regulation, in particular, for tissue specificity and species specificity of gene regulation within the primate lineage. The results provide motivation for future research with directions including TE-mediated species-specific gene regulation due to differentially co-opted ancient TEs, TE occurrences at TAD anchors for non-CTCF boundary elements, and the specific mechanisms behind tissue-specific epigenetics of TEs that shapes tissue-specific gene expression.