The Role of KRAB-ZFPs in Transposable Element Repression and Mammalian Evolution

Kruppel-associated box zinc-finger proteins (KRAB-ZFPs) make up the largest family of transcription factors in humans. These proteins emerged in the last common ancestor of coelacanth and tetrapods, and have expanded and diversified in the mammalian lineage. Although their mechanism of transcriptional repression has been well studied for over a decade, the DNA-binding activities and the biological functions of these proteins have been largely unexplored. Recent large-scale ChIP-seq studies and loss-of-function experiments have revealed that KRAB-ZFPs play a major role in the recognition and transcriptional silencing of transposable elements (TEs), consistent with an ‘arms race model’ of KRAB-ZFP evolution against invading TEs. However, this model is insufficient to explain the evolution of many KRAB-ZFPs that appear to domesticate TEs for novel host functions. We highlight some of the mammalian regulatory innovations driven by specific KRAB-ZFPs, including genomic imprinting, meiotic recombination hotspot choice, and placental growth. KRAB-ZFPs make up the largest class of DNA-binding transcription factors in mammals. The KRAB-domain is a potent transcriptional repression domain that functions via recruitment of the TRIM28 corepressor which recruits heterochromatin-inducing machinery. KRAB-ZFPs are rapidly evolving in mammals, primarily at the level of expansion of KRAB-ZFP gene clusters, likely in response to invading waves of TEs. The majority of KRAB-ZFPs (∼2/3 in humans) interact with TEs via specific DNA-binding motifs. Loss-of-function studies of KRAB-ZFP corepressors and individual KRAB-ZFPs demonstrate that KRAB-ZFPs transcriptionally repress target TEs and prevent latent enhancer/promoter activity within TEs from affecting nearby genes. The continuous cycle of KRAB-ZFP evolution against TEs provides a driving force for new adaptations in mammals.