KRAB-ZFPs and the establishment of lineage- and species-specific gene regulatory networks (360G-Wellcome-206688_Z_17_Z)

KRAB-ZFPs constitute a large yet neglected family of proteins with around 350 members in human and mouse. Collectively, they target transposable elements and until recently were thought to be mostly involved in their transcriptional repression in embryonic stem cells. During my post-doctoral work, I unveiled the binding sites of most (222) human KRAB-ZFPs, but the role played by the majority of them could not be fully explained by current theorems. Instead, we found that many target ancient transposable elements which often contain regulatory platforms; we also obtained correlative evidence that these could affect the expression of nearby genes. We hypothesize that evolutionary conserved KRAB-ZFPs can use their heterochromatin-inducing capabilities to modify accessibility of these transposable element-derived regulatory elements. We propose to functionally demonstrate this potential by using large scale enhancer screens in multiple cell types. Furthermore, we want to follow-up on these findings by genetic manipulations aimed at characterizing the biological processes affected by a few KRAB-ZFPs, including the generation of mouse models. Finally, we want to better understand the evolution dynamics of KRAB-ZFP binding sites and verify if they can lead to lineage- and species-specific rewiring of gene regulatory networks.