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Zinc-finger nuclease-driven targeted integration into mammalian genomes using donors with limited chromosomal homology

Orlando, Salvatore J., Santiago, Yolanda, DeKelver, Russell C., Freyvert, Yevgeniy, Boydston, Elizabeth A., Moehle, Erica A., Choi, Vivian M., Gopalan, Sunita M., Lou, Jacqueline F., Li, James, Miller, Jeffrey C., Holmes, Michael C., Gregory, Philip D., Urnov, Fyodor D., Cost, Gregory J.·2010·Nucleic Acids Research
DOI 10.1093/nar/gkq512PMC PMC2926620
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Figure 1. Homology-based targeted integration using short-homology synthetic donors. (A) Diagram of ZFNs binding to the AAVS1 locus. (B) Schematic of short-homology synthetic donor creation via PCR and comparison with plasmid donor. (C) Targeted integration at AAVS1 with plasmid and short-homology synthetic donors assayed by PCR. Homology region length is given in base pairs for linear donors and kilobase pairs for plasmid donors. DNA type is either plasmid (Pl) or linear phosphorothioate (S). Co-transfection of 7 µg of a linear donor is stoichiometrically equal to 50 µg of this plasmid donor. As PCR preferentially amplifies shorter molecules, the assay slightly under-represents the true frequency of targeted integration. (D) Targeted integration at AAVS1 with plasmid and short-homology synthetic donors assayed by Southern blot. Genomic DNAs used as a PCR template in (B) were analyzed directly by probing for the 5′ region of AAVS1 homology present in the donor plasmid. A map of the locus below the blot shows the position of the homology arms (white box), the probe (grey region with in the white box), the XmnI sites used for digestion. The XmnI fragment from wild-type chromosome is 5336 bp; from an integrated chromosome, 6881 bp. (E) Targeted integration using short-homology synthetic donors at IL2Rγ. Obligate FokI heterodimer ZFNs are referred to as HiFi ZFNs. The DNA type descriptor refers to either plasmid (Pl) or whether the ends of linear donors are normal (O) or phosphorothioate DNA (S). Co-transfection of 5 µg of a linear donor is approximately stoichiometrically equal to 50 µg of this plasmid donor. Homology region length is given in base pairs for linear donors and kilobase pairs for plasmid donors. For (C, D and F) the percentage of modified chromosomes is shown below each lane in black text.
Figure 1. Homology-based targeted integration using short-homology synthetic donors. (A) Diagram of ZFNs binding to the AAVS1 locus. (B) Schematic of short-homology synthetic donor creation via PCR and comparison with plasmid donor. (C) Targeted integration at AAVS1 with plasmid and short-homology synthetic donors assayed by PCR. Homology region length is given in base pairs for linear donors and kilobase pairs for plasmid donors. DNA type is either plasmid (Pl) or linear phosphorothioate (S). Co-transfection of 7 µg of a linear donor is stoichiometrically equal to 50 µg of this plasmid donor. As PCR preferentially amplifies shorter molecules, the assay slightly under-represents the true frequency of targeted integration. (D) Targeted integration at AAVS1 with plasmid and short-homology synthetic donors assayed by Southern blot. Genomic DNAs used as a PCR template in (B) were analyzed directly by probing for the 5′ region of AAVS1 homology present in the donor plasmid. A map of the locus below the blot shows the position of the homology arms (white box), the probe (grey region with in the white box), the XmnI sites used for digestion. The XmnI fragment from wild-type chromosome is 5336 bp; from an integrated chromosome, 6881 bp. (E) Targeted integration using short-homology synthetic donors at IL2Rγ. Obligate FokI heterodimer ZFNs are referred to as HiFi ZFNs. The DNA type descriptor refers to either plasmid (Pl) or whether the ends of linear donors are normal (O) or phosphorothioate DNA (S). Co-transfection of 5 µg of a linear donor is approximately stoichiometrically equal to 50 µg of this plasmid donor. Homology region length is given in base pairs for linear donors and kilobase pairs for plasmid donors. For (C, D and F) the percentage of modified chromosomes is shown below each lane in black text.CC BY-NC · PubMed Central
Figure 2. The effect of donor topology, methylation and terminal sequence homology on targeted integration of a small, HindIII site-containing patch. (A) K562 cells were transfected with supercoiled or linearized (ScaI) plasmid donors containing either 500 or 250 bp of flanking AAVS1 homology. Targeted integration was assayed by HindIII digestion of PCR-amplified chromosomes into 1041 and 918 bp products. (B) Targeted integration with topologically relaxed and differently methylated donors. Donor type is indicated as follows: supercoiled, sc’d; relaxed with topoisomerase I, relax; dam and dcm methylated, d&d; CpG methylated, CpG. Targeted integration was assayed by SalI (GS), HindIII (AAVS1) or XbaI (CCR5) digestion of PCR-amplified chromosomes as appropriate. (C) Insertion of a pGK-GFP-pA transgene into the AAVS1 locus. The length of the homology arms was varied as indicated and targeted integration measured by PCR. PCR amplification of the wild-type locus produces a 1953 bp product; integration of the transgene results in a 3498 bp product. (D) Insertion of a small HindIII-containing patch into the AAVS1 locus in K562 cells. The length of the homology arms was varied as indicated and targeted integration measured by PCR and HindIII digestion. Targeted integration produces 1041 and 918 bp HindIII digestion products. (E) Targeted integration into AAVS1 using donors with and without terminal sequence homology and extendibility. Targeted integration was performed with equimolar amounts of donors containing 250 or 100 bp of flanking homology. Circular donors are supercoiled plasmids, linear donors are PCR products. Linear donors tailed with dideoxycytidine are indicated as lin.+ddC. HindIII site integration was assayed by digestion as above. (F) The targeted integration signal is generated in the cell not during PCR. The indicated samples were mixed after DNA preparation but before PCR. HindIII site integration was assayed as above. The percentage of modified chromosomes is shown below each lane in black text.
Figure 2. The effect of donor topology, methylation and terminal sequence homology on targeted integration of a small, HindIII site-containing patch. (A) K562 cells were transfected with supercoiled or linearized (ScaI) plasmid donors containing either 500 or 250 bp of flanking AAVS1 homology. Targeted integration was assayed by HindIII digestion of PCR-amplified chromosomes into 1041 and 918 bp products. (B) Targeted integration with topologically relaxed and differently methylated donors. Donor type is indicated as follows: supercoiled, sc’d; relaxed with topoisomerase I, relax; dam and dcm methylated, d&d; CpG methylated, CpG. Targeted integration was assayed by SalI (GS), HindIII (AAVS1) or XbaI (CCR5) digestion of PCR-amplified chromosomes as appropriate. (C) Insertion of a pGK-GFP-pA transgene into the AAVS1 locus. The length of the homology arms was varied as indicated and targeted integration measured by PCR. PCR amplification of the wild-type locus produces a 1953 bp product; integration of the transgene results in a 3498 bp product. (D) Insertion of a small HindIII-containing patch into the AAVS1 locus in K562 cells. The length of the homology arms was varied as indicated and targeted integration measured by PCR and HindIII digestion. Targeted integration produces 1041 and 918 bp HindIII digestion products. (E) Targeted integration into AAVS1 using donors with and without terminal sequence homology and extendibility. Targeted integration was performed with equimolar amounts of donors containing 250 or 100 bp of flanking homology. Circular donors are supercoiled plasmids, linear donors are PCR products. Linear donors tailed with dideoxycytidine are indicated as lin.+ddC. HindIII site integration was assayed by digestion as above. (F) The targeted integration signal is generated in the cell not during PCR. The indicated samples were mixed after DNA preparation but before PCR. HindIII site integration was assayed as above. The percentage of modified chromosomes is shown below each lane in black text.CC BY-NC · PubMed Central
Figure 3. Analysis of the overhang types created by ZFNs. (A) Scheme to determine ZFN overhangs. A supercoiled plasmid with a ZFN cleavage site is cut by a titration of in vitro transcribed and translated ZFNs. ZFN-linearized plasmids are purified by gel electrophoresis, 5′ overhangs filled in with Klenow polymerase (grey nucleotides), and the resulting blunt ends ligated. The mixture is subjected to high-throughput DNA sequencing. (B) Overhang types generated by a control restriction enzyme (HindIII) and three of the ZFN pairs used in this work. For clarity, only one DNA strand is shown. Enzyme binding sites are shown in grey; only the flanking three nucleotides are shown for ZFN binding sites. Primary cleavage sites, black triangles; secondary and tertiary cleavage sites, dark and light grey triangles, respectively; deletions, Δ. Microhomology within the target site can prevent unambiguous deduction of the overhang type. In such situations the possible overhangs are shown as joined triangles. Either of the two indicated thymidine residues may have been deleted after HindIII digestion.
Figure 3. Analysis of the overhang types created by ZFNs. (A) Scheme to determine ZFN overhangs. A supercoiled plasmid with a ZFN cleavage site is cut by a titration of in vitro transcribed and translated ZFNs. ZFN-linearized plasmids are purified by gel electrophoresis, 5′ overhangs filled in with Klenow polymerase (grey nucleotides), and the resulting blunt ends ligated. The mixture is subjected to high-throughput DNA sequencing. (B) Overhang types generated by a control restriction enzyme (HindIII) and three of the ZFN pairs used in this work. For clarity, only one DNA strand is shown. Enzyme binding sites are shown in grey; only the flanking three nucleotides are shown for ZFN binding sites. Primary cleavage sites, black triangles; secondary and tertiary cleavage sites, dark and light grey triangles, respectively; deletions, Δ. Microhomology within the target site can prevent unambiguous deduction of the overhang type. In such situations the possible overhangs are shown as joined triangles. Either of the two indicated thymidine residues may have been deleted after HindIII digestion.CC BY-NC · PubMed Central
Figure 4. Targeted DNA integration via non-homologous end joining. (A) Diagram of ZFN cleavage at AAVS1 resulting in 4-bp 5′ overhangs followed by in vivo ligation of a complimentary-overhang donor. The donor contains both BamHI and EcoRI restriction enzyme sites. (B) NHEJ capture at the AAVS1 locus in K562 cells. Three 10-fold dilutions (40–0.4 µM) of donor DNA with the indicated overhang types were co-transfected with the AAVS1 ZFNs. The PCR amplicons were cut with EcoRI, producing 327 and 258 bp products from amplicons with insertion of the oligonucleotide. All donors in this experiment contain terminal phosphorothioate residues. (C) NHEJ capture at the GS locus in CHO-K1 cells. Four 10-fold dilutions of donor DNAs (40–0.04 µM) with the indicated overhang types and phosphorothioate usage were co-transfected with the GS ZFNs. The PCR amplicons were cut with BamHI, producing 288 and 106 bp products from amplicons with insertion of the oligonucleotide. For (B and C), the percentage of modified chromosomes is shown below each lane in black text; the position of the molecular weight markers used is shown in grey text on the left of the gel.
Figure 4. Targeted DNA integration via non-homologous end joining. (A) Diagram of ZFN cleavage at AAVS1 resulting in 4-bp 5′ overhangs followed by in vivo ligation of a complimentary-overhang donor. The donor contains both BamHI and EcoRI restriction enzyme sites. (B) NHEJ capture at the AAVS1 locus in K562 cells. Three 10-fold dilutions (40–0.4 µM) of donor DNA with the indicated overhang types were co-transfected with the AAVS1 ZFNs. The PCR amplicons were cut with EcoRI, producing 327 and 258 bp products from amplicons with insertion of the oligonucleotide. All donors in this experiment contain terminal phosphorothioate residues. (C) NHEJ capture at the GS locus in CHO-K1 cells. Four 10-fold dilutions of donor DNAs (40–0.04 µM) with the indicated overhang types and phosphorothioate usage were co-transfected with the GS ZFNs. The PCR amplicons were cut with BamHI, producing 288 and 106 bp products from amplicons with insertion of the oligonucleotide. For (B and C), the percentage of modified chromosomes is shown below each lane in black text; the position of the molecular weight markers used is shown in grey text on the left of the gel.CC BY-NC · PubMed Central
Figure 5. Targeted DNA integration at deletions via non-homologous end joining. (A) Diagram of dual ZFN cleavage at POU5F1 resulting in 5-bp 5′ overhangs from the left ZFN pair and 4-bp 5′ overhangs from the right ZFN pair followed by in vivo ligation of a complimentary-overhang donor. The donor contains both BamHI and EcoRI restriction enzyme sites. (B) NHEJ capture at a POU5F1 deletion in K562 cells and at BAK in CHO-K1 cells. Left (L) and right (R) ZFN pairs were transfected individually and in combination (LR), with (+) and without donor co-transfection. The sizes of significant PCR products are shown on the right side of the gels. As deletions are heterogeneous, their expected sizes are indicated with tildes. Due to the relatively small deletion made in POU5F1, amplification of the wild-type locus is seen (1956 bp). The deletion quantitiation shown below the gel is from an independent analysis of cell pools described in the main text; the deletion frequency in lane 6 was not measured. (C) Restriction enzyme digestion confirms targeted integration into the POU5F1 and BAK deletions. PCR reactions from lanes 3, 6, 7, 11, 14 and 15 in (B) were divided into thirds, one-third was left uncut (blank), one third was digested with BamHI (B), and one-third was digested with EcoRI (E). The sizes of BamHI and EcoRI digestion products are shown on the right side of the gel, POU5F1 in the left column, BAK in the right. The amount of digested DNA was determined by densitometry.
Figure 5. Targeted DNA integration at deletions via non-homologous end joining. (A) Diagram of dual ZFN cleavage at POU5F1 resulting in 5-bp 5′ overhangs from the left ZFN pair and 4-bp 5′ overhangs from the right ZFN pair followed by in vivo ligation of a complimentary-overhang donor. The donor contains both BamHI and EcoRI restriction enzyme sites. (B) NHEJ capture at a POU5F1 deletion in K562 cells and at BAK in CHO-K1 cells. Left (L) and right (R) ZFN pairs were transfected individually and in combination (LR), with (+) and without donor co-transfection. The sizes of significant PCR products are shown on the right side of the gels. As deletions are heterogeneous, their expected sizes are indicated with tildes. Due to the relatively small deletion made in POU5F1, amplification of the wild-type locus is seen (1956 bp). The deletion quantitiation shown below the gel is from an independent analysis of cell pools described in the main text; the deletion frequency in lane 6 was not measured. (C) Restriction enzyme digestion confirms targeted integration into the POU5F1 and BAK deletions. PCR reactions from lanes 3, 6, 7, 11, 14 and 15 in (B) were divided into thirds, one-third was left uncut (blank), one third was digested with BamHI (B), and one-third was digested with EcoRI (E). The sizes of BamHI and EcoRI digestion products are shown on the right side of the gel, POU5F1 in the left column, BAK in the right. The amount of digested DNA was determined by densitometry.CC BY-NC · PubMed Central

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Metadata

Authors
Orlando, S. J., Santiago, Y., DeKelver, R. C., Freyvert, Y., Boydston, E. A., Moehle, E. A., Choi, V. M., Gopalan, S. M., Lou, J. F., Li, J., Miller, J. C., Holmes, M. C., Gregory, P. D., Urnov, F. D., & Cost, G. J.
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2010-06-08
Volume
38
Issue
15
Pages
e152-e152
ISSN
  • 1362-4962
  • 0305-1048
DOI
10.1093/nar/gkq512
PMC
PMC2926620
Cited by
174
References
5
Language
en
Licence
creativecommons.org/licenses/by-nc/2.5 (vor, 2344 d)

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