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An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons

Abstract

Throughout evolution primate genomes have been modified by waves of retrotransposon insertions1,2,3. For each wave, the host eventually finds a way to repress retrotransposon transcription and prevent further insertions. In mouse embryonic stem cells, transcriptional silencing of retrotransposons requires KAP1 (also known as TRIM28) and its repressive complex, which can be recruited to target sites by KRAB zinc-finger (KZNF) proteins such as murine-specific ZFP809 which binds to integrated murine leukaemia virus DNA elements and recruits KAP1 to repress them4,5. KZNF genes are one of the fastest growing gene families in primates and this expansion is hypothesized to enable primates to respond to newly emerged retrotransposons6,7. However, the identity of KZNF genes battling retrotransposons currently active in the human genome, such as SINE-VNTR-Alu (SVA)8 and long interspersed nuclear element 1 (L1)9, is unknown. Here we show that two primate-specific KZNF genes rapidly evolved to repress these two distinct retrotransposon families shortly after they began to spread in our ancestral genome. ZNF91 underwent a series of structural changes 8–12 million years ago that enabled it to repress SVA elements. ZNF93 evolved earlier to repress the primate L1 lineage until 12.5 million years ago when the L1PA3-subfamily of retrotransposons escaped ZNF93’s restriction through the removal of the ZNF93-binding site. Our data support a model where KZNF gene expansion limits the activity of newly emerged retrotransposon classes, and this is followed by mutations in these retrotransposons to evade repression, a cycle of events that could explain the rapid expansion of lineage-specific KZNF genes.

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Figure 1: SVAs and L1PAs are derepressed in a non-primate cellular environment.
Figure 2: SVA elements are repressed by primate-specific ZNF91.
Figure 3: L1PA elements are repressed by primate-specific ZNF93.
Figure 4: Dynamic patterns of co-evolution between ZNFs and target retrotransposons.

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Gene Expression Omnibus

Data deposits

The data discussed in this publication have been deposited in the NCBI Gene Expression Omnibus and are accessible through GEO Series accession number GSE60211.

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Acknowledgements

This work was supported by California Institute of Regenerative Medicine (CIRM) facility awards (FA1-00617, CL1-00506-1.2) and scholar awards (TG2-01157) to F.M.J.J. and D.G. and F.M.J.J. also received a Human Frontier Science Program Postdoctoral fellowship (LT000689). D.H. is an Investigator of the Howard Hughes Medical Institute. S.K. is supported by the California Institute for Quantitative Biosciences, A.D.E. was supported by TCGA U24 24010-443720, M.H. by EMBO ALTF 292-2011, and B.P. and N.N. by ENCODE U41HG004568. We thank F. Wianny and C. Dehay (Lyon University) for the LYON-ES1 macaque embryonic stem cells; M. Oshimura and T. Inoue (Tottori University) for the E14(hChr11) trans-chromosomic embryonic stem cells, N. Pourmand and the UCSC genome sequencing center; B. Nazario (UCSC Institute for the Biology of Stem Cells) for flow cytometry assistance; M. Batzer (LSU) and K. Han (Dankook University) for L1CER sequences; L. Carbone (OHSU) for gibbon genomic DNA; A. Smit (ISB, Seattle) for discussions on L1PA evolution; D. Segal (UC Davis) for advice on ZNF mutations; H. Kazazian, D. Hancks and J. Goodier (JHMI) for retrotransposition plasmids and advice; K. Tygi, C. Vizenor, J. Rosenkrantz, W. Novey, S. Kyane and B. Mylenek for technical assistance and the entire Haussler laboratory for discussions and support.

Author information

Authors and Affiliations

Authors

Contributions

F.M.J.J., D.G., D.H. and S.R.S. designed and analysed the experiments. F.M.J.J. performed RNA-seq, ChIP-seq and reintroduction of primate ZNFs in trans-chromosomic mESCs; D.G. performed ZNF cloning, luciferase reporter and retrotransposition assays; N.N., D.G., A.D.E. and B.P. performed resequencing and analysis to complete the ZNF91 and ZNF93 loci in various primates; N.N. and B.P. reconstructed the evolutionary history of ZNF91 and ZNF93 ZNF domains; M.H. generated a Repeatmasker UCSC-Browser and hub, ZNF-binding site predictions and VNTR length analysis; S.K. processed and analysed RNA-seq and ChIP-seq data; A.D.E. analysed SVA numbers in great apes and SVA–gene-expression correlations. F.M.J.J., D.G., S.R.S. and D.H. wrote the manuscript.

Corresponding author

Correspondence to David Haussler.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 KAP1 associates with recently emerged transposable elements.

a, Immunoblot incubated with anti-KAP1 antibody loaded with 1% input and eluates of KAP1-ChIP or IgG-ChIP derived from hESC lysates. b, Diagram showing numbers of KAP1 peaks identified in two independent biological replicates and common peaks. c, Distribution of 9,174 KAP1-ChIP-seq peaks over various DNA elements. d, Distribution of retrotransposon classes among KAP1-ChIP peaks from hESCs (left) or genome-wide (right). e, KAP1 and H3K4me3 ChIP-seq and RNA-seq coverage tracks for a representative region on human chromosome 11 in hESCs (white- or grey-shaded) and TC11-mESCs (yellow-shaded). Blue arrows, derepressed retrotransposons; black arrows, re-activated transcription; red vertical shading, reactivated SVAs; orange shading, reactivated LTR12C. Blue and tan in RNA-seq tracks indicate positive and negative strand transcripts, respectively. Note that while the majority of SVAs display aberrant H3K4me3 signal, for unclear reasons not all SVAs display aberrant transcription in TC11-mESCs. Rep, biological replicate; sup, supernatant; TSS, transcription start site.

Extended Data Figure 2 Mouse KAP1 associates with mouse-specific retrotransposons in mouse ESCs.

a, Distribution of KAP1-ChIP-Seq reads from mESCs (left) and the mouse genome (right) for retrotransposon families as defined by RepeatMasker (http://www.repeatmasker.org/). b, UCSC Browser image displaying ChIP-seq tracks for input (grey shading) and KAP1 (red shading) as well as gene annotation and repeat element tracks for a region on mouse chromosome 1. Blue shading, KAP1-positive active mouse L1-subtypes45; purple shading, KAP1-positive active intracisternal A-particle (IAP) retrotransposons. LINES, long interspersed nuclear elements; LTR, long terminal repeat; MMERVK10C, mouse endogenous retrovirus subtype K10C; RMER, medium reiteration frequency repetitive sequence; SINES, short interspersed nuclear elements; TEs, transposable elements.

Extended Data Figure 3 Selection of primate-specific KZNF genes with high expression in hESCs.

a, Schematic of primate-specific KRAB zinc-finger genes subdivided in different clades based on previous analysis7. KZNFs shown in b are highlighted in red. b, DESeq-calculated gene expression levels for the 17 highest expressed KRAB zinc-finger genes in hESCs (dark blue) and macaque ESCs (light blue), subdivided by clades.

Extended Data Figure 4 The SVA VNTR domain is necessary and sufficient for ZNF91-mediated repression of luciferase activity.

a–c, Schematic of SV40–luciferase constructs used (left) and relative luciferase activity after transfection of the indicated constructs in mESCs (right). a, SVA and SINE-R are strong enhancers (n = 6 biological replicates). b, Deletion analysis reveals the VNTR of SVA is required for ZNF91-mediated reporter regulation. Luciferase activity in the presence of ZNF91 expressed as a ratio of that observed for empty vector with the same reporter. Biological replicates: no VNTR, n = 9; partial VNTR, n = 3; no hex/Alu, n = 2; no hex, n = 2; full length SVA, n = 15; SINE-R, n = 3. Empty vector is set to 100% for comparison. c, 1.5 VNTR repeats are sufficient to confer ZNF91-mediated regulation on an OCT4Enh–SV40–luciferase-reporter. n = 3 biological replicates. **P < 0.01; error bars are s.e.m.

Extended Data Figure 5 SVA is specifically repressed in vivo by ZNF91.

a, b, Normalized DESeq basemean values for H3K4me3 ChIP-seq (a) and RNA-seq (b) for retrotransposon classes that showed a significant change in ZNF91-transfected TC11-mESCs relative to empty vector. SVAs were the only transposable elements that showed a significant decrease in H3K4me3 and RNA-seq values. **Benjamini–Hochberg adjusted-P < 0.01. c, UCSC browser images for a representative SVA element, promoter and L1PA4 element, showing H3K4me3 ChIP-seq signal for hESCs (grey), TC11-mESCs transfected with empty vector (yellow), pools of primate-specific KRAB zinc-fingers (green) and ZNF91 (red). TSSC4: tumor-suppressing subtransferable candidate 4.

Extended Data Figure 6 Evolutionary history of ZNF91.

a, The phylogenetic tree used in multiple sequence alignment and ancestral reconstruction of ZNF91 (Supplementary Information File 3). ‘hu 1.1’, ‘ch 1.1’ and ‘go 1.1’ represent human, chimpanzee and gorilla domain 6, respectively, ‘hu 1.2’, ‘ch 1.2’, ‘go 1.2’ represent human, chimpanzee and gorilla domains 7–12, respectively, and ‘hu 2’, ‘ch 2’ and ‘go 2’ represent the ZNF91 sequence from start to domain 5, a breakpoint, and from domain 13 to the end (see Methods). Ancestors are labelled with first letters of leaf species below them, for example, HCG is a human–chimp–gorilla ancestor. b, Immunoblot incubated with anti-HA antibody on lysates of HEK293FT cells transfected with HA-tagged human, great ape, hominine and macaque ZNF91 proteins or lysates transfected with an empty vector and pCAG–GFP. Asterisks denote reconstructed ancestral proteins. c, ZNF91 domain deletion analysis showing relative luciferase activities on the SVA-D–SV40 luciferase reporter after transfection of empty vector or ZNF91 deletion constructs in mESCs. Error bars are standard deviation. Numbers in parenthesis indicate zinc-fingers present in the ZNF91 deletion construct. *P < 0.05; **P < 0.01. Biological replicates: empty vector, n = 42; ZNF91 (1–11), n = 4; ZNF91 (1–24), n = 7; ZNF91 (1–30), n = 4; ZNF91 (1, 2, 23–36), n = 3.

Extended Data Figure 7 L1PA4 elements are repressed by primate-specific ZNF93.

a, Relative luciferase activity on a L1PA4– and a OCT4-enhancer–SV40–luciferase-reporter after transfection of 14 KZNFs in mESCs. Significance measured relative to empty vector. n = 3 biological replicates; *P < 0.05; **P < 0.01; error bars are s.e.m. b, Immunoblot showing that ChIP with antibody ab104878 predominantly reacts with a protein of 70 kDa (left panel) and co-immunoprecipitates KAP1 (right panel). HC, heavy chain of IgG. c, Immunoblot demonstrating that ChIP with ab104878 detects overexpressed ZNF93 in 46c mESCs as a 70 kDa protein. d, Repeat Browser (see Methods) displaying ChIP-seq coverage tracks for ab104878 (ZNF93; yellow shading) and KAP1 (blue shading) for a selection of KAP1-bound retrotransposons. e, ChIP-qPCR for amplicons in L1PA4 and LTR12C elements on chromosome 11 in TC11-mESCs after transfection with an empty vector or ZNF93 and ChIP with ab104878. ChIP enrichment is plotted as percentage of input. n = 3 biological replicates; *P < 0.05; error bars are s.e.m.

Extended Data Figure 8 Reconstruction of the evolutionary history of ZNF93.

a, Schematic based on the multiple sequence alignment of ZNF93 orthologues (Supplementary Information File 4). Red shaded area, deletion of zinc-fingers; green shaded area, gain of zinc-fingers; green stripes, gained zinc-fingers; dark blue stripes, zinc-fingers that changed contact residues in the lineage to humans; light blue stripes, changes in other lineages; brown stripes, zinc-fingers with different binding residues between macaques and gibbons, with gibbons sharing the great ape conformation. For this last group of zinc-fingers, it is unknown (represented with a ? symbol) whether the change happened in monkeys or in the LCA of gibbons and great apes after the divergence of Old-World monkeys (see Methods). Asterisks denote reconstructed ancestral proteins. b, Relative OCT4-enhancer–SV40p–luciferase activity for reporters with the indicated L1PA4-derived sequences after co-transfection of an empty vector or various ZNF93 constructs. **P < 0.01; error bars are s.e.m.

Extended Data Figure 9 Schematic of L1Hs retrotranspostion assay.

a, Schematic of constructs tested indicating the site of 129L1PA4 transplant into L1Hs and concept of L1–GFP assay24 in which GFP expression marks cells where a transfected L1 episome has retrotransposed into a HEK293 cell’s chromosomes. ORF, open reading frame; CMV, cytomegalovirus promoter; SD, splice donor; SA, splice acceptor; PvuII, restriction enzyme site.

Extended Data Figure 10 Evolutionary history of L1PA3-6030, L1PA3-6160 and the VNTR size in SVA.

a, Phylogenetic tree, rooted on L1PA4, generated using the Minimum Evolution method42 for fifty 3′-end sequences of L1PA3-6030 and L1PA3-6160, and three 3′-end sequences for L1PA2 and L1PA4. b, Bar graphs showing the number of SVA-_A through SVA_F insertions in each great ape genome. c, Distribution of VNTR size for untruncated SVA elements in the human genome plotted for each SVA-subfamily. The number of untruncated elements identified for each subtype is indicated.

Supplementary information

Supplementary Information 1

This file contains construction details and associated primers and gene sequences for the plasmids used in this study. (PDF 238 kb)

Supplementary Information 2

This file contains primers used for generating sequence data to fill in genome assembly gaps around ZNF91 and ZNF93 in various primate genomes. (PDF 60 kb)

Supplementary Information 3

This file contains full multiple sequence alignment for ZNF91. (PDF 435 kb)

Supplementary Information 4

This file contains full multiple sequence alignment for ZNF93. (PDF 195 kb)

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Jacobs, F., Greenberg, D., Nguyen, N. et al. An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons. Nature 516, 242–245 (2014). https://doi.org/10.1038/nature13760

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