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KRAB/KAP1-mediated gene regulation in mammalian physiology and human diseases

Final Report Summary - KRABNKAP (KRAB/KAP1-mediated gene regulation in mammalian physiology and human diseases)

Transposable elements (TEs) may account for up to two-thirds of the human genome, and as genomic threats they are subjected to epigenetic control mechanisms engaged from the earliest stages of embryonic development. Under the auspices of this ERC grant, we determined that an important component of this process is the sequence-specific recognition of TEs by KRAB-containing zinc finger proteins (KRAB-ZFPs), a large family of tetrapod-restricted transcription factors that act by recruiting inducers of heterochromatin formation and DNA methylation. We further demonstrated that KRAB-ZFPs and their cofactor KAP1 exert a marked influence on the transcription dynamics of embryonic stem cells via their docking of repressor complexes at TE-contained regulatory sequences. It is generally held that, beyond this early embryonic period, TEs become permanently silenced, and that the evolutionary selection of KRAB-ZFPs and other TE controllers is the result of a simple evolutionary arms race between the host and these genetics invaders. We invalidated this dual assumption and demonstrated instead that KRAB-ZFPs are the instruments of a massive enterprise of TE domestication, whereby transposon-based regulatory sequences and their cellular ligands establish species-specific transcription regulation networks that influence multiple aspects of human development and physiology.