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CRISPR-SURF: discovering regulatory elements by deconvolution of CRISPR tiling screen data

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Data availability

The data are available at SRA under project number PRJNA494935.

References

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    Canver, M. C. et al. Nature 527, 192–197 (2015).

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    Fulco, C. P. et al. Science 354, 769–773 (2016).

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    Simeonov, D. R. et al. Nature 549, 111–115 (2017).

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    Korkmaz, G. et al. Nat. Biotechnol. 34, 192–198 (2016).

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Acknowledgements

We thank R. Kurita and Y. Nakamura (RIKEN BioResource Center, Tsukuba, Japan) for sharing HUDEP-2 cells. L.P. is supported by NHGRI Career Development Award R00 HG008399 and CEGS RM1HG009490. D.E.B. is support by NIH R03 DK109232, NIH DP2 OD022716, NIH P01 HL032262, the Burroughs Wellcome Fund, and the Doris Duke Charitable Foundation. J.K.J. is supported by NIH R35 GM118158, NIH RM1 HG009490, and the Desmond and Ann Heathwood MGH Research Scholar Award. M.C.C. is supported by NIDDK Award F30-DK103359. J.M.E. is supported by NIH NHGRI 1K99HG009917-01 and the Harvard Society of Fellows.

Author information

J.Y.H. and L.P. conceived of and developed the CRISPR-SURF framework. M.A.C., M.C.C., and F.S. performed the experiments. C.P.F., D.P., R.F., K.C., J.A.G., L.B., S.H.O., J.M.E., and E.S.L. provided statistical and experimental expertise. J.K.J., L.P., and D.E.B. oversaw the project and offered feedback and guidance. J.Y.H., L.P., D.E.B., and J.K.J. wrote the manuscript with input from all other authors.

Competing interests

J.K.J. has financial interests in Beam Therapeutics, Editas Medicine, Endcadia, Monitor Biotechnologies (formerly known as Beacon Genomics), Pairwise Plants, Poseida Therapeutics, and Transposagen Biopharmaceuticals. J.K.J. holds equity in EpiLogic Therapeutics. J.K.J.’s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. J.K.J. is a member of the Board of Directors of the American Society of Gene and Cell Therapy, and an inventor on patents and patent applications covering CRISPR-based nucleases and gene regulatory proteins. E.S.L. serves on the Board of Directors for Codiak BioSciences and Neon Therapeutics, and on the Scientific Advisory Board of F-Prime Capital Partners and Third Rock Ventures; he is also affiliated with several nonprofit organizations, including through his service on the Board of Directors of the Innocence Project and Biden Cancer Initiative and the Board of Trustees for the Parker Institute for Cancer Immunotherapy. He has served and continues to serve on various federal advisory committees. The Broad Institute, which E.S.L. directs, holds patents and has filed patent applications on technologies related to other aspects of CRISPR.

Correspondence to Daniel E. Bauer or Luca Pinello.

Integrated supplementary information

  1. Supplementary Figure 1 Reanalysis of a CRISPR–Cas9 tiling screen from Canver et al.1.

    (a) An overview of the BCL11A CRISPR–Cas9 enhancer dissection tiling screen. (b) Zoom-in panels of DHS +55, +58, +62, and BCL11A exon 2 to highlight critical regions identified by CRISPR-SURF. All significant regions identified with FDR < 0.05. All panels are shown at same scale.

  2. Supplementary Figure 2 Reanalysis of a CRISPRi tiling screen from Fulco et al.2.

    (a) An overview of the MYC CRISPRi enhancer discovery tiling screen. (b) Zoom-in panels of MYC TSS, e1–e7, and r1 (regions identified in ref. 2) along with newly identified regions by CRISPR-SURF (SURF1 and SURF2). All significant regions identified with FDR < 0.05. All panels are shown at same scale.

  3. Supplementary Figure 3 Reanalysis of a CRISPRa tiling screen from Simeonov et al.3.

    (a) An overview of the IL2RA CRISPRa enhancer discovery tiling screen. (b) Zoom-in panels of IL2RA TSS and CaREs 1–6 (regions identified in ref. 3) along with regions newly identified by CRISPR-SURF (SURF3 and SURF4). All significant regions identified with FDR < 0.05. All panels are shown at same scale.

  4. Supplementary Figure 4 CRISPR-SURF analysis of parallel CRISPRi and CRISPR–Cas9 DHS tiling screens targeted to the BCL11A locus.

    (a) An overview of the BCL11A CRISPRi and CRISPR–Cas9 DHS tiling screens. (b) Shown are zoom-in panels of BCL11A exon 2 and common significant regions (FDR < 0.05) between the CRISPRi and CRISPR–Cas9 tiling screens as determined by CRISPR-SURF.

Supplementary Information

  1. Supplementary Text and Figures

    Supplementary Figures 1–4 and Supplementary Notes 1–7

  2. Reporting Summary

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Fig. 1: CRISPR-SURF deconvolution framework.
Supplementary Figure 1: Reanalysis of a CRISPR–Cas9 tiling screen from Canver et al.1.
Supplementary Figure 2: Reanalysis of a CRISPRi tiling screen from Fulco et al.2.
Supplementary Figure 3: Reanalysis of a CRISPRa tiling screen from Simeonov et al.3.
Supplementary Figure 4: CRISPR-SURF analysis of parallel CRISPRi and CRISPR–Cas9 DHS tiling screens targeted to the BCL11A locus.