KRAB-ZNFs: controllers of transposable element activity and safeguards of genome integrity

Transposable elements (TEs) are mobile DNA sequences that can move within genomes, shaping genomic diversity and evolution. However, their movement can cause DNA breaks and structural rearrangements, leading to genomic instability. As a defense mechanism, KRAB zinc finger proteins (KRAB-ZNFs) evolved as key repressors of TEs, binding specific TE sequences to silence them through epigenetic mechanisms. This dynamic interplay between TEs and KRAB-ZNFs has fueled an evolutionary arms race, promoting rapid diversification of both elements. Consequently, TE and KRAB-ZNF interactions have profoundly influenced genome architecture, regulatory networks, and species-specific traits across vertebrates. This thesis explores the versatility of KRAB-ZNF functions in the human genome, suggesting roles that extend beyond their established involvement in TE transposition repression. While previous research has primarily focused on KRAB-ZNFs as regulators of gene expression as an alternative model, this work broadens the scope to investigate additional roles, including the KRAB-ZNF mediated control of TEs involved in stem cell pluripotency and protecting our genome from excessive meiotic recombination. The findings presented here aim to inform and inspire further research into KRAB-ZNFs’ diverse contributions to gene expression network innovation, genome stability and human genome evolution.