Abstract

KRAB zinc finger proteins (KZFPs) are the largest subfamily of DNA binding factors in mammals. They emerged at the dawn of tetrapods and have since expanded at a dramatic pace, with new members found at every phylogenetic branch; illustrative of that fact, only 80 genes are shared between mouse and human out of their respective 350. They primarily target endogenous transposable elements and are involved in their transcriptional control in embryonic stem cells through the recruitment of TRIM28 and the subsequent deposition of repressive epigenetic marks (H3K9me3 and DNA methylation). KZF Ps and transposable elements are thought to be locked in a fast-paced evolutionary arms race, with new KZF Ps continuously emerging to tackle the genomic threat of invading transposable elements. Interestingly, many KZF Ps are targeting evolutionary conserved remains of transposable elements, millions of years after these have lost all replication potential. Moreover, these largely degraded transposable elements still contain docking sites for transcription factors and are found to be epigenetically active in certain cellular contexts; therefore, they could participate in the rewiring of transcriptional networks by acting as enhancers or alternative promoters. Expression patterns of KZF Ps are quite diverse and not restricted to embryonic stem cells, hinting at roles outside the transcriptional repression of transposable elements during embryogenesis. We are hypothesizing that one such role is to toggle accessibility of transposable element-derived enhancers, resulting in the regulation of nearby genes in a cell-type specific fashion.

In this talk I will discuss the latest developments emerging from my lab regarding this topic. We have processed large-scale genomic and transcriptomic datasets to generate high-resolution maps of the diversity of KZFP presence and activity between cell types. This will be supplemented with a discussion of the fine-grained evolutionary history of KZF Ps and their targets, showcasing unsuspected patterns of evolution in rodents. I will present some of our latest data from functional studies on a few specific KZF Ps underlying important biological processes such as immunity or development. Notably, we have identified complex regulatory dynamics between KZF Ps and their targets, as well as counter examples to the arms race hypothesis. Overall, our results improve our understanding of how KZF Ps contribute to the evolution of gene regulatory networks, with implications for the interpretation of mutations found within the non-coding genome.