The battle inside our genome:Controlling transposable elements and the evolution of human gene regulatory networks

Transposable elements (TEs) are mobile genetic elements that accumulated in various families over the course of evolution and function as cis-regulatory elements in a species- and cell type-specific manner. The KRAB zinc finger (KZNF) gene family evolved in parallel and is specialized in repressing TEs. In this thesis we studied the regulatory role of KZNF proteins and TEs in human embryonic stem cells (hESCs) and neurons. First, we analyzed hESCs and cortical and midbrain dopamine organoids transcriptionally and epigenetically. We showed that both KZNF genes and TEs show a highly cell type-specific and correlating expression pattern. Profiling of enhancer-associated H3K27ac revealed several TEs families that may function as cell type-specific cis-regulators. Next were identified which KZNF proteins are essential for repression of a primate-specific TE family, called SVA. We demonstrated through chromatin immuno precipitation (ChIP) followed by sequencing that ZNF91 and ZNF611 have the highest SVA binding capacity. Through genetic ablation of ZNF91 and/or ZNF611 in hESCs we showed that only in the absence of ZNF91 evolutionary young SVA elements became activated and regulated gene expression in cis and trans. Most striking was the selective upregulation of clusters of KZNF genes in proximity of reactivated SVA elements. This suggests that derepressed TEs elicit a defense response of the host aimed at controlling a TE invasion. Together these findings contribute to our understanding of the evolutionary arms race between the host and TEs and lay ground to further study how they impacted the evolution of novel structures and functions.