The endovirome and its epigenetic controllers, or the species-specificity of human biology and of its pathological deviations

More than 5 million integrants derived from transposable elements (TEs) are dispersed in the human genome, hosting at least a quarter of its candidate cis-regulatory elements (CREs) and transcription factor (TF) binding sites. In higher vertebrates, the co-option of these TE sequences was made possible through domestication of their regulatory activity by KRAB-containing zinc finger proteins (KZFPs). KZFPs emerged some 400 million years ago in the ancestral tetrapod genome and constitute the largest family of TFs encoded by mammals, with close to 400 family members in human alone. The KZFP-TE system, both components of which display high levels of lineage-specificity, is an essential driver of the evolution of gene regulatory networks, and influences most aspects of human biology examined so far. Furthermore, a series of chassé-croisés between KZFP genes and TE sequences has generated a remarkable level of novelty in the mechanistic of human genome regulation. Finally, as expected from its broad involvement in the control of human biology, the KZFP/TE system is intimately linked to its pathological deviations, notably cancer.