KRAB Zinc Finger Proteins coordinate across evolutionary time scales to battle retroelements

KRAB Zinc Finger Proteins (KZNFs) are the largest and fastest evolving family of human transcription factors1,2. The evolution of this protein family is closely linked to the tempo of retrotransposable element (RTE) invasions, with specific KZNF family members demonstrated to transcriptionally repress specific families of RTEs3,4. The competing selective pressures between RTEs and the KZNFs results in evolutionary arms races whereby KZNFs evolve to recognize RTEs, while RTEs evolve to escape KZNF recognition5. Evolutionary analyses of the primate-specific RTE family L1PA and two of its KZNF binders, ZNF93 and ZNF649, reveal specific nucleotide and amino changes consistent with an arms race scenario. Our results suggest a model whereby ZNF649 and ZNF93 worked together to target independent motifs within the L1PA RTE lineage. L1PA elements eventually escaped the concerted action of this KZNF “team” over ∼30 million years through two distinct mechanisms: a slow accumulation of point mutations in the ZNF649 binding site and a rapid, massive deletion of the entire ZNF93 binding site.

[1]  Philip M. Kim,et al.  A structural approach reveals how neighbouring C2H2 zinc fingers influence DNA binding specificity , 2015, Nucleic acids research.

[2]  D. Trono Transposable Elements, Polydactyl Proteins, and the Genesis of Human-Specific Transcription Networks. , 2015, Cold Spring Harbor Symposia on Quantitative Biology.

[3]  Yixuan Wang,et al.  The Role of KRAB-ZFPs in Transposable Element Repression and Mammalian Evolution. , 2017, Trends in genetics : TIG.

[4]  Stéphane Boissinot,et al.  Molecular evolution and tempo of amplification of human LINE-1 retrotransposons since the origin of primates. , 2005, Genome research.

[5]  Timothy L. Bailey,et al.  Gene expression Advance Access publication May 4, 2011 DREME: motif discovery in transcription factor ChIP-seq data , 2011 .

[6]  D. Trono,et al.  KRAB zinc-finger proteins contribute to the evolution of gene regulatory networks , 2017, Nature.

[7]  Andrew Emili,et al.  Multiparameter functional diversity of human C2H2 zinc finger proteins , 2016, Genome research.

[8]  Xiaodong Cheng,et al.  A placental growth factor is silenced in mouse embryos by the zinc finger protein ZFP568 , 2017, Science.

[9]  Nevan J Krogan,et al.  CRISPR Interference Efficiently Induces Specific and Reversible Gene Silencing in Human iPSCs. , 2016, Cell stem cell.

[10]  Dan Yang,et al.  ZNF649, a novel Kruppel type zinc-finger protein, functions as a transcriptional suppressor. , 2005, Biochemical and biophysical research communications.

[11]  S. Goff,et al.  Embryonic stem cells use ZFP809 to silence retroviral DNAs , 2009, Nature.

[12]  R. Tjian,et al.  The TATA-binding protein and associated factors are integral components of the RNA polymerase I transcription factor, SL1 , 1992, Cell.

[13]  Xiaodong Cheng,et al.  DNA Conformation Induces Adaptable Binding by Tandem Zinc Finger Proteins , 2018, Cell.

[14]  David Haussler,et al.  An evolutionary arms race between KRAB zinc finger genes 91/93 and SVA/L1 retrotransposons , 2014, Nature.

[15]  Mihai Albu,et al.  Identification of C2H2-ZF binding preferences from ChIP-seq data using RCADE , 2015, Bioinform..

[16]  Mona Singh,et al.  De novo prediction of DNA-binding specificities for Cys2His2 zinc finger proteins , 2013, Nucleic acids research.

[17]  Laurie Gordon,et al.  A comprehensive catalog of human KRAB-associated zinc finger genes: insights into the evolutionary history of a large family of transcriptional repressors. , 2006, Genome research.

[18]  James H. Thomas,et al.  Coevolution of retroelements and tandem zinc finger genes. , 2011, Genome research.

[19]  G. Faulkner,et al.  Transposable elements in the mammalian embryo: pioneers surviving through stealth and service , 2016, Genome Biology.

[20]  Helen M. Rowe,et al.  Transposable Elements and Their KRAB-ZFP Controllers Regulate Gene Expression in Adult Tissues. , 2016, Developmental cell.