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

Abstract

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 function of these proteins has 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.

DeviaTE: Assembly‐free analysis and visualization of mobile genetic element composition

“…Depending on the TE family and the host species, copy numbers can range from a few to hundreds of thousands of insertions (Biémont & Vieira, 2006;Pritham & Feschotte, 2007). Although defence mechanisms against these selfish elements have emerged (Brennecke et al, 2007;Yang, Wang, & Macfarlan, 2017), TEs have proven to be highly successful invaders. Hence, most genomes contain large fractions of TEs.…”

piRNA clusters need a minimum size to control transposable element invasions

“…Alternatively, some organism may have multiple layers of defence against TEs. For example Kruppelassociated box zinc-finger proteins (KRAB-ZFPs) may silence TEs in some mammals (Yang et al, 2017). KRAB-ZFPs bind to TE sequences and induce heterochromatin formation (Yang et al, 2017).…”

“…For example Kruppelassociated box zinc-finger proteins (KRAB-ZFPs) may silence TEs in some mammals (Yang et al, 2017). KRAB-ZFPs bind to TE sequences and induce heterochromatin formation (Yang et al, 2017). However, some TEs continue to be active even when targeted by KRAB-ZFPs and KRAB-ZFPs only target some TE families (Yang et al, 2017).…”

“…KRAB-ZFPs bind to TE sequences and induce heterochromatin formation (Yang et al, 2017). However, some TEs continue to be active even when targeted by KRAB-ZFPs and KRAB-ZFPs only target some TE families (Yang et al, 2017). Furthermore, it not clear if KRAB-ZFPs are mostly responsible for the longterm maintenance of TE repression or if they may also silence a newly invading TE.…”

“…Furthermore, it not clear if KRAB-ZFPs are mostly responsible for the longterm maintenance of TE repression or if they may also silence a newly invading TE. It is however difficult to see how the sequence specificity of KRAB-ZFPs, which is determined by tandem arrays of C2H2 zinc fingers (Yang et al, 2017), could rapidly adapt to the sequence of a newly invading TE. Thus in contrast to the piRNA pathway, which provides a generalized defence mechanism capable of trapping and silencing any mobile element, KRAB-ZFPs likely constitute a more specialized defence layer, requiring adaptation of the DNA binding sites to the sequence of each novel TE.…”