Advertisement

Dissecting Tissue-Specific Super-Enhancers by Integrating Genome-Wide Analyses and CRISPR/Cas9 Genome Editing

  • Kyung Hyun Yoo
  • Lothar Hennighausen
  • Ha Youn Shin
Article

Abstract

Recent advances in genome-wide sequencing technologies have provided researchers with unprecedented opportunities to discover the genomic structures of gene regulatory units in living organisms. In particular, the integration of ChIP-seq, RNA-seq, and DNase-seq techniques has facilitated the mapping of a new class of regulatory elements. These elements, called super-enhancers, can regulate cell-type-specific gene sets and even fine-tune gene expression regulation in response to external stimuli, and have become a hot topic in genome biology. However, there is scant genetic evidence demonstrating their unique biological relevance and the mechanisms underlying these biological functions. In this review, we describe a robust genome-wide strategy for mapping cell-type-specific enhancers or super-enhancers in the mammary genome. In this strategy, genome-wide screening of active enhancer clusters that are co-occupied by mammary-enriched transcription factors, co-factors, and active enhancer marks is used to identify bona fide mammary tissue-specific super-enhancers. The in vivo function of these super-enhancers and their associated regulatory elements may then be investigated in various ways using the advanced CRISPR/Cas9 genome-editing technology. Based on our experience targeting various mammary genomic sites using CRISPR/Cas9 in mice, we comprehensively discuss the molecular consequences of the different targeting methods, such as the number of gRNAs and the dependence on their simultaneous or sequential injections. We also mention the considerations that are essential for obtaining accurate results and shed light on recent progress that has been made in developing modified CRISPR/Cas9 genome-editing techniques. In the future, the coupling of advanced genome-wide sequencing and genome-editing technologies could provide new insights into the complex genetic regulatory networks involved in mammary-gland development.

Keywords

Super-enhancer Genome-wide analysis CRISPR/Cas9 Cell type-specific gene regulation Mammary gland development 

Abbreviations

SE

Super-enhancer

Notes

Acknowledgements

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2018R1C1B6001117) and the Collaborative Genome Program for Fostering New Post-Genome Industry of the National Research Foundation (NRF) funded by the Ministry of Science and ICT (MSIT) (NRF-2017M3C9A6044519).

References

  1. 1.
    Shlyueva D, Stampfel G, Stark A. Transcriptional enhancers: from properties to genome-wide predictions. Nat Rev Genet. 2014;15(4):272–86.  https://doi.org/10.1038/nrg3682.CrossRefPubMedGoogle Scholar
  2. 2.
    Boyle AP, Davis S, Shulha HP, Meltzer P, Margulies EH, Weng Z, et al. High-resolution mapping and characterization of open chromatin across the genome. Cell. 2008;132(2):311–22.  https://doi.org/10.1016/j.cell.2007.12.014.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Johnson DS, Mortazavi A, Myers RM, Wold B. Genome-wide mapping of in vivo protein-DNA interactions. Science. 2007;316(5830):1497–502.  https://doi.org/10.1126/science.1141319.CrossRefPubMedGoogle Scholar
  4. 4.
    Robertson G, Hirst M, Bainbridge M, Bilenky M, Zhao Y, Zeng T, et al. Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing. Nat Methods. 2007;4(8):651–7.  https://doi.org/10.1038/nmeth1068.CrossRefPubMedGoogle Scholar
  5. 5.
    Ong CT, Corces VG. Enhancer function: new insights into the regulation of tissue-specific gene expression. Nat Rev Genet. 2011;12(4):283–93.  https://doi.org/10.1038/nrg2957.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ong CT, Corces VG. Enhancers: emerging roles in cell fate specification. EMBO Rep. 2012;13(5):423–30.  https://doi.org/10.1038/embor.2012.52.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Morin R, Bainbridge M, Fejes A, Hirst M, Krzywinski M, Pugh T, et al. Profiling the HeLa S3 transcriptome using randomly primed cDNA and massively parallel short-read sequencing. BioTechniques. 2008;45(1):81–94.  https://doi.org/10.2144/000112900.CrossRefPubMedGoogle Scholar
  8. 8.
    Wang Z, Gerstein M, Snyder M. RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet. 2009;10(1):57–63.  https://doi.org/10.1038/nrg2484.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Urnov FD, Miller JC, Lee YL, Beausejour CM, Rock JM, Augustus S, et al. Highly efficient endogenous human gene correction using designed zinc-finger nucleases. Nature. 2005;435(7042):646–51.  https://doi.org/10.1038/nature03556.CrossRefPubMedGoogle Scholar
  10. 10.
    Miller JC, Holmes MC, Wang J, Guschin DY, Lee YL, Rupniewski I, et al. An improved zinc-finger nuclease architecture for highly specific genome editing. Nat Biotechnol. 2007;25(7):778–85.  https://doi.org/10.1038/nbt1319.CrossRefPubMedGoogle Scholar
  11. 11.
    Boch J, Scholze H, Schornack S, Landgraf A, Hahn S, Kay S, et al. Breaking the code of DNA binding specificity of TAL-type III effectors. Science. 2009;326(5959):1509–12.  https://doi.org/10.1126/science.1178811.CrossRefPubMedGoogle Scholar
  12. 12.
    Moscou MJ, Bogdanove AJ. A simple cipher governs DNA recognition by TAL effectors. Science. 2009;326(5959):1501.  https://doi.org/10.1126/science.1178817.CrossRefPubMedGoogle Scholar
  13. 13.
    Christian M, Cermak T, Doyle EL, Schmidt C, Zhang F, Hummel A, et al. Targeting DNA double-strand breaks with TAL effector nucleases. Genetics. 2010;186(2):757–61.  https://doi.org/10.1534/genetics.110.120717.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Miller JC, Tan S, Qiao G, Barlow KA, Wang J, Xia DF, et al. A TALE nuclease architecture for efficient genome editing. Nat Biotechnol. 2011;29(2):143–8.  https://doi.org/10.1038/nbt.1755.CrossRefPubMedGoogle Scholar
  15. 15.
    Mojica FJ, Diez-Villasenor C, Garcia-Martinez J, Soria E. Intervening sequences of regularly spaced prokaryotic repeats derive from foreign genetic elements. J Mol Evol. 2005;60(2):174–82.  https://doi.org/10.1007/s00239-004-0046-3.CrossRefPubMedGoogle Scholar
  16. 16.
    Pourcel C, Salvignol G, Vergnaud G. CRISPR elements in Yersinia pestis acquire new repeats by preferential uptake of bacteriophage DNA, and provide additional tools for evolutionary studies. Microbiology. 2005;151(Pt 3):653–63.  https://doi.org/10.1099/mic.0.27437-0.CrossRefPubMedGoogle Scholar
  17. 17.
    Bolotin A, Quinquis B, Sorokin A, Ehrlich SD. Clustered regularly interspaced short palindrome repeats (CRISPRs) have spacers of extrachromosomal origin. Microbiology. 2005;151(Pt 8):2551–61.  https://doi.org/10.1099/mic.0.28048-0.CrossRefPubMedGoogle Scholar
  18. 18.
    Wiedenheft B, Sternberg SH, Doudna JA. RNA-guided genetic silencing systems in bacteria and archaea. Nature. 2012;482(7385):331–8.  https://doi.org/10.1038/nature10886.CrossRefPubMedGoogle Scholar
  19. 19.
    Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337(6096):816–21.  https://doi.org/10.1126/science.1225829.CrossRefPubMedGoogle Scholar
  20. 20.
    Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, et al. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;339(6121):819–23.  https://doi.org/10.1126/science.1231143.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE, et al. RNA-guided human genome engineering via Cas9. Science. 2013;339(6121):823–6.  https://doi.org/10.1126/science.1232033.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Wang H, Yang H, Shivalila CS, Dawlaty MM, Cheng AW, Zhang F, et al. One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell. 2013;153(4):910–8.  https://doi.org/10.1016/j.cell.2013.04.025.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ran FA, Cong L, Yan WX, Scott DA, Gootenberg JS, Kriz AJ, et al. In vivo genome editing using Staphylococcus aureus Cas9. Nature. 2015;520(7546):186–91.  https://doi.org/10.1038/nature14299.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013;153(2):307–19.  https://doi.org/10.1016/j.cell.2013.03.035.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-Andre V, Sigova AA, et al. Super-enhancers in the control of cell identity and disease. Cell. 2013;155(4):934–47.  https://doi.org/10.1016/j.cell.2013.09.053.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Yin JW, Wang G. The mediator complex: a master coordinator of transcription and cell lineage development. Development. 2014;141(5):977–87.  https://doi.org/10.1242/dev.098392.CrossRefPubMedGoogle Scholar
  27. 27.
    Vahedi G, Kanno Y, Furumoto Y, Jiang K, Parker SC, Erdos MR, et al. Super-enhancers delineate disease-associated regulatory nodes in T cells. Nature. 2015;520(7548):558–62.  https://doi.org/10.1038/nature14154.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Siersbaek R, Rabiee A, Nielsen R, Sidoli S, Traynor S, Loft A, et al. Transcription factor cooperativity in early adipogenic hotspots and super-enhancers. Cell Rep. 2014;7(5):1443–55.  https://doi.org/10.1016/j.celrep.2014.04.042.CrossRefPubMedGoogle Scholar
  29. 29.
    Adam RC, Yang H, Rockowitz S, Larsen SB, Nikolova M, Oristian DS, et al. Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice. Nature. 2015;521(7552):366–70.  https://doi.org/10.1038/nature14289.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Huang J, Liu X, Li D, Shao Z, Cao H, Zhang Y, et al. Dynamic control of enhancer repertoires drives lineage and stage-specific transcription during hematopoiesis. Dev Cell. 2016;36(1):9–23.  https://doi.org/10.1016/j.devcel.2015.12.014.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Shin HY, Willi M, HyunYoo K, Zeng X, Wang C, Metser G, et al. Hierarchy within the mammary STAT5-driven Wap super-enhancer. Nat Genet. 2016;48(8):904–11.  https://doi.org/10.1038/ng.3606.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Pittius CW, Sankaran L, Topper YJ, Hennighausen L. Comparison of the regulation of the whey acidic protein gene with that of a hybrid gene containing the whey acidic protein gene promoter in transgenic mice. Mol Endocrinol. 1988;2(11):1027–32.  https://doi.org/10.1210/mend-2-11-1027.CrossRefPubMedGoogle Scholar
  33. 33.
    Robinson GW, Kang K, Yoo KH, Tang Y, Zhu BM, Yamaji D, et al. Coregulation of genetic programs by the transcription factors NFIB and STAT5. Mol Endocrinol. 2014;28(5):758–67.  https://doi.org/10.1210/me.2012-1387.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Zhou J, Chehab R, Tkalcevic J, Naylor MJ, Harris J, Wilson TJ, et al. Elf5 is essential for early embryogenesis and mammary gland development during pregnancy and lactation. EMBO J. 2005;24(3):635–44.  https://doi.org/10.1038/sj.emboj.7600538.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Lee HK, Willi M, Wang C, Yang CM, Smith HE, Liu C, et al. Functional assessment of CTCF sites at cytokine-sensing mammary enhancers using CRISPR/Cas9 gene editing in mice. Nucleic Acids Res. 2017;45(8):4606–18.  https://doi.org/10.1093/nar/gkx185.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Willi M, Yoo KH, Reinisch F, Kuhns TM, Lee HK, Wang C, et al. Facultative CTCF sites moderate mammary super-enhancer activity and regulate juxtaposed gene in non-mammary cells. Nat Commun. 2017;8:16069.  https://doi.org/10.1038/ncomms16069.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Mansour MR, Abraham BJ, Anders L, Berezovskaya A, Gutierrez A, Durbin AD, et al. Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science. 2014;346(6215):1373–7.  https://doi.org/10.1126/science.1259037.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Shi J, Whyte WA, Zepeda-Mendoza CJ, Milazzo JP, Shen C, Roe JS, et al. Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation. Genes Dev. 2013;27(24):2648–62.  https://doi.org/10.1101/gad.232710.113.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Drier Y, Cotton MJ, Williamson KE, Gillespie SM, Ryan RJ, Kluk MJ, et al. An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma. Nat Genet. 2016;48(3):265–72.  https://doi.org/10.1038/ng.3502.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Parker SC, Stitzel ML, Taylor DL, Orozco JM, Erdos MR, Akiyama JA, et al. Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. Proc Natl Acad Sci U S A. 2013;110(44):17921–6.  https://doi.org/10.1073/pnas.1317023110.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Achour M, Le Gras S, Keime C, Parmentier F, Lejeune FX, Boutillier AL, et al. Neuronal identity genes regulated by super-enhancers are preferentially down-regulated in the striatum of Huntington's disease mice. Hum Mol Genet. 2015;24(12):3481–96.  https://doi.org/10.1093/hmg/ddv099.CrossRefPubMedGoogle Scholar
  42. 42.
    Le Gras S, Keime C, Anthony A, Lotz C, De Longprez L, Brouillet E, et al. Altered enhancer transcription underlies Huntington's disease striatal transcriptional signature. Sci Rep. 2017;7:42875.  https://doi.org/10.1038/srep42875.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Shin HY. Targeting super-enhancers for disease treatment and diagnosis. Mol Cells. 2018;41(6):506–14.  https://doi.org/10.14348/molcells.2018.2297.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Zeng L, Zhou MM. Bromodomain: an acetyl-lysine binding domain. FEBS Lett. 2002;513(1):124–8.CrossRefGoogle Scholar
  45. 45.
    Zuber V, Bettella F, Witoelar A, Consortium P, Cruk G, Consortium B, et al. Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer. BMC Genomics. 2017;18(1):270.  https://doi.org/10.1186/s12864-017-3620-y.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Glodzik D, Morganella S, Davies H, Simpson PT, Li Y, Zou X, et al. A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers. Nat Genet. 2017;49(3):341–8.  https://doi.org/10.1038/ng.3771.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Loven J, Hoke HA, Lin CY, Lau A, Orlando DA, Vakoc CR, et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell. 2013;153(2):320–34.  https://doi.org/10.1016/j.cell.2013.03.036.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Ohba S, He X, Hojo H, McMahon AP. Distinct transcriptional programs underlie Sox9 regulation of the mammalian chondrocyte. Cell Rep. 2015;12(2):229–43.  https://doi.org/10.1016/j.celrep.2015.06.013.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Liu CF, Lefebvre V. The transcription factors SOX9 and SOX5/SOX6 cooperate genome-wide through super-enhancers to drive chondrogenesis. Nucleic Acids Res. 2015;43(17):8183–203.  https://doi.org/10.1093/nar/gkv688.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Wang AH, Juan AH, Ko KD, Tsai PF, Zare H, Dell’Orso S, et al. The elongation factor Spt6 maintains ESC pluripotency by controlling super-enhancers and counteracting Polycomb proteins. Mol Cell. 2017;68(2):398–413 e6.  https://doi.org/10.1016/j.molcel.2017.09.016.CrossRefPubMedGoogle Scholar
  51. 51.
    Lomberk G, Blum Y, Nicolle R, Nair A, Gaonkar KS, Marisa L, et al. Distinct epigenetic landscapes underlie the pathobiology of pancreatic cancer subtypes. Nat Commun. 2018;9(1):1978.  https://doi.org/10.1038/s41467-018-04383-6.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Suzuki HI, Young RA, Sharp PA. Super-enhancer-mediated RNA processing revealed by integrative MicroRNA network analysis. Cell. 2017;168(6):1000–14 e15.  https://doi.org/10.1016/j.cell.2017.02.015.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Chapuy B, McKeown MR, Lin CY, Monti S, Roemer MG, Qi J, et al. Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma. Cancer Cell. 2013;24(6):777–90.  https://doi.org/10.1016/j.ccr.2013.11.003.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Pelish HE, Liau BB, Nitulescu II, Tangpeerachaikul A, Poss ZC, Da Silva DH, et al. Mediator kinase inhibition further activates super-enhancer-associated genes in AML. Nature. 2015;526(7572):273–6.  https://doi.org/10.1038/nature14904.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Das S, Senapati P, Chen Z, Reddy MA, Ganguly R, Lanting L, et al. Regulation of angiotensin II actions by enhancers and super-enhancers in vascular smooth muscle cells. Nat Commun. 2017;8(1):1467.  https://doi.org/10.1038/s41467-017-01629-7.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Nakamura Y, Hattori N, Iida N, Yamashita S, Mori A, Kimura K, et al. Targeting of super-enhancers and mutant BRAF can suppress growth of BRAF-mutant colon cancer cells via repression of MAPK signaling pathway. Cancer Lett. 2017;402:100–9.  https://doi.org/10.1016/j.canlet.2017.05.017.CrossRefPubMedGoogle Scholar
  57. 57.
    Gelato KA, Schockel L, Klingbeil O, Ruckert T, Lesche R, Toedling J, et al. Super-enhancers define a proliferative PGC-1alpha-expressing melanoma subgroup sensitive to BET inhibition. Oncogene. 2018;37(4):512–21.  https://doi.org/10.1038/onc.2017.325.CrossRefPubMedGoogle Scholar
  58. 58.
    Andricovich J, Perkail S, Kai Y, Casasanta N, Peng W, Tzatsos A. Loss of KDM6A activates super-enhancers to induce gender-specific squamous-like pancreatic Cancer and confers sensitivity to BET inhibitors. Cancer Cell. 2018;33(3):512–26 e8.  https://doi.org/10.1016/j.ccell.2018.02.003.CrossRefGoogle Scholar
  59. 59.
    Gerlach D, Tontsch-Grunt U, Baum A, Popow J, Scharn D, Hofmann MH, et al. The novel BET bromodomain inhibitor BI 894999 represses super-enhancer-associated transcription and synergizes with CDK9 inhibition in AML. Oncogene. 2018;37(20):2687–701.  https://doi.org/10.1038/s41388-018-0150-2.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Nakagawa M, Shaffer AL 3rd, Ceribelli M, Zhang M, Wright G, Huang DW, et al. Targeting the HTLV-I-regulated BATF3/IRF4 transcriptional network in adult T cell leukemia/lymphoma. Cancer Cell. 2018;34(2):286–97e10.  https://doi.org/10.1016/j.ccell.2018.06.014.CrossRefPubMedGoogle Scholar
  61. 61.
    Chen D, Zhao Z, Huang Z, Chen DC, Zhu XX, Wang YZ, et al. Super enhancer inhibitors suppress MYC driven transcriptional amplification and tumor progression in osteosarcoma. Bone Res. 2018;6:11.  https://doi.org/10.1038/s41413-018-0009-8.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Li Y, Rivera CM, Ishii H, Jin F, Selvaraj S, Lee AY, et al. CRISPR reveals a distal super-enhancer required for Sox2 expression in mouse embryonic stem cells. PLoS One. 2014;9(12):e114485.  https://doi.org/10.1371/journal.pone.0114485.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Hnisz D, Schuijers J, Lin CY, Weintraub AS, Abraham BJ, Lee TI, et al. Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers. Mol Cell. 2015;58(2):362–70.  https://doi.org/10.1016/j.molcel.2015.02.014.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Moorthy SD, Davidson S, Shchuka VM, Singh G, Malek-Gilani N, Langroudi L, et al. Enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes. Genome Res. 2017;27(2):246–58.  https://doi.org/10.1101/gr.210930.116.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Dave K, Sur I, Yan J, Zhang J, Kaasinen E, Zhong F, et al. Mice deficient of Myc super-enhancer region reveal differential control mechanism between normal and pathological growth. Elife. 2017;6.  https://doi.org/10.7554/eLife.23382.
  66. 66.
    Huang J, Li K, Cai W, Liu X, Zhang Y, Orkin SH, et al. Dissecting super-enhancer hierarchy based on chromatin interactions. Nat Commun. 2018;9(1):943.  https://doi.org/10.1038/s41467-018-03279-9.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Schuijers J, Manteiga JC, Weintraub AS, Day DS, Zamudio AV, Hnisz D, et al. Transcriptional dysregulation of MYC reveals common enhancer-docking mechanism. Cell Rep. 2018;23(2):349–60.  https://doi.org/10.1016/j.celrep.2018.03.056.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Pantera H, Moran JJ, Hung HA, Pak E, Dutra A, Svaren J. Regulation of the neuropathy-associated Pmp22 gene by a distal super-enhancer. Hum Mol Genet. 2018;27(16):2830–9.  https://doi.org/10.1093/hmg/ddy191.CrossRefPubMedGoogle Scholar
  69. 69.
    Metser G, Shin HY, Wang C, Yoo KH, Oh S, Villarino AV, et al. An autoregulatory enhancer controls mammary-specific STAT5 functions. Nucleic Acids Res. 2016;44(3):1052–63.  https://doi.org/10.1093/nar/gkv999.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Zeng X, Willi M, Shin HY, Hennighausen L, Wang C. Lineage-specific and non-specific cytokine-sensing genes respond differentially to the master regulator STAT5. Cell Rep. 2016;17(12):3333–46.  https://doi.org/10.1016/j.celrep.2016.11.079.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Willi M, Yoo KH, Wang C, Trajanoski Z, Hennighausen L. Differential cytokine sensitivities of STAT5-dependent enhancers rely on Stat5 autoregulation. Nucleic Acids Res. 2016;44(21):10277–91.  https://doi.org/10.1093/nar/gkw844.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Shin HY, Wang C, Lee HK, Yoo KH, Zeng X, Kuhns T, et al. CRISPR/Cas9 targeting events cause complex deletions and insertions at 17 sites in the mouse genome. Nat Commun. 2017;8:15464.  https://doi.org/10.1038/ncomms15464.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Sung YH, Kim JM, Kim HT, Lee J, Jeon J, Jin Y, et al. Highly efficient gene knockout in mice and zebrafish with RNA-guided endonucleases. Genome Res. 2014;24(1):125–31.  https://doi.org/10.1101/gr.163394.113.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    McVey M, Lee SE. MMEJ repair of double-strand breaks (director's cut): deleted sequences and alternative endings. Trends Genet. 2008;24(11):529–38.  https://doi.org/10.1016/j.tig.2008.08.007.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Zhou J, Wang J, Shen B, Chen L, Su Y, Yang J, et al. Dual sgRNAs facilitate CRISPR/Cas9-mediated mouse genome targeting. FEBS J. 2014;281(7):1717–25.  https://doi.org/10.1111/febs.12735.CrossRefPubMedGoogle Scholar
  76. 76.
    Fujii W, Kawasaki K, Sugiura K, Naito K. Efficient generation of large-scale genome-modified mice using gRNA and CAS9 endonuclease. Nucleic Acids Res. 2013;41(20):e187.  https://doi.org/10.1093/nar/gkt772.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Wang L, Shao Y, Guan Y, Li L, Wu L, Chen F, et al. Large genomic fragment deletion and functional gene cassette knock-in via Cas9 protein mediated genome editing in one-cell rodent embryos. Sci Rep. 2015;5:17517.  https://doi.org/10.1038/srep17517.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Hara S, Kato T, Goto Y, Kubota S, Tamano M, Terao M, et al. Microinjection-based generation of mutant mice with a double mutation and a 0.5 Mb deletion in their genome by the CRISPR/Cas9 system. J Reprod Dev. 2016;62(5):531–6.  https://doi.org/10.1262/jrd.2016-058.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Kosicki M, Tomberg K, Bradley A. Repair of double-strand breaks induced by CRISPR-Cas9 leads to large deletions and complex rearrangements. Nat Biotechnol. 2018;36(8):765–71.  https://doi.org/10.1038/nbt.4192.CrossRefPubMedGoogle Scholar
  80. 80.
    Lee H, Kim JS. Unexpected CRISPR on-target effects. Nat Biotechnol. 2018;36(8):703–4.  https://doi.org/10.1038/nbt.4207.CrossRefPubMedGoogle Scholar
  81. 81.
    Bolukbasi MF, Gupta A, Wolfe SA. Creating and evaluating accurate CRISPR-Cas9 scalpels for genomic surgery. Nat Methods. 2016;13(1):41–50.  https://doi.org/10.1038/nmeth.3684.CrossRefPubMedGoogle Scholar
  82. 82.
    Kanchiswamy CN, Maffei M, Malnoy M, Velasco R, Kim JS. Fine-tuning next-generation genome editing tools. Trends Biotechnol. 2016;34(7):562–74.  https://doi.org/10.1016/j.tibtech.2016.03.007.CrossRefPubMedGoogle Scholar
  83. 83.
    Kim D, Bae S, Park J, Kim E, Kim S, Yu HR, et al. Digenome-seq: genome-wide profiling of CRISPR-Cas9 off-target effects in human cells. Nat Methods. 2015;12(3):237–43, 1 p following 43.  https://doi.org/10.1038/nmeth.3284.CrossRefPubMedGoogle Scholar
  84. 84.
    Crosetto N, Mitra A, Silva MJ, Bienko M, Dojer N, Wang Q, et al. Nucleotide-resolution DNA double-strand break mapping by next-generation sequencing. Nat Methods. 2013;10(4):361–5.  https://doi.org/10.1038/nmeth.2408.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Wang X, Wang Y, Wu X, Wang J, Wang Y, Qiu Z, et al. Unbiased detection of off-target cleavage by CRISPR-Cas9 and TALENs using integrase-defective lentiviral vectors. Nat Biotechnol. 2015;33(2):175–8.  https://doi.org/10.1038/nbt.3127.CrossRefPubMedGoogle Scholar
  86. 86.
    Gabriel R, Lombardo A, Arens A, Miller JC, Genovese P, Kaeppel C, et al. An unbiased genome-wide analysis of zinc-finger nuclease specificity. Nat Biotechnol. 2011;29(9):816–23.  https://doi.org/10.1038/nbt.1948.CrossRefPubMedGoogle Scholar
  87. 87.
    Frock RL, Hu J, Meyers RM, Ho YJ, Kii E, Alt FW. Genome-wide detection of DNA double-stranded breaks induced by engineered nucleases. Nat Biotechnol. 2015;33(2):179–86.  https://doi.org/10.1038/nbt.3101.CrossRefPubMedGoogle Scholar
  88. 88.
    Tsai SQ, Zheng Z, Nguyen NT, Liebers M, Topkar VV, Thapar V, et al. GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases. Nat Biotechnol. 2015;33(2):187–97.  https://doi.org/10.1038/nbt.3117.CrossRefPubMedGoogle Scholar
  89. 89.
    Kim HK, Song M, Lee J, Menon AV, Jung S, Kang YM, et al. In vivo high-throughput profiling of CRISPR-Cpf1 activity. Nat Methods. 2017;14(2):153–9.  https://doi.org/10.1038/nmeth.4104.CrossRefPubMedGoogle Scholar
  90. 90.
    Kim E, Koo T, Park SW, Kim D, Kim K, Cho HY, et al. In vivo genome editing with a small Cas9 orthologue derived from campylobacter jejuni. Nat Commun. 2017;8:14500.  https://doi.org/10.1038/ncomms14500.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Thakore PI, D'Ippolito AM, Song L, Safi A, Shivakumar NK, Kabadi AM, et al. Highly specific epigenome editing by CRISPR-Cas9 repressors for silencing of distal regulatory elements. Nat Methods. 2015;12(12):1143–9.  https://doi.org/10.1038/nmeth.3630.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Gilbert LA, Larson MH, Morsut L, Liu Z, Brar GA, Torres SE, et al. CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell. 2013;154(2):442–51.  https://doi.org/10.1016/j.cell.2013.06.044.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Konermann S, Brigham MD, Trevino A, Hsu PD, Heidenreich M, Cong L, et al. Optical control of mammalian endogenous transcription and epigenetic states. Nature. 2013;500(7463):472–6.  https://doi.org/10.1038/nature12466.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Hilton IB, D'Ippolito AM, Vockley CM, Thakore PI, Crawford GE, Reddy TE, et al. Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat Biotechnol. 2015;33(5):510–7.  https://doi.org/10.1038/nbt.3199.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Perez-Pinera P, Kocak DD, Vockley CM, Adler AF, Kabadi AM, Polstein LR, et al. RNA-guided gene activation by CRISPR-Cas9-based transcription factors. Nat Methods. 2013;10(10):973–6.  https://doi.org/10.1038/nmeth.2600.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Maeder ML, Linder SJ, Cascio VM, Fu Y, Ho QH, Joung JK. CRISPR RNA-guided activation of endogenous human genes. Nat Methods. 2013;10(10):977–9.  https://doi.org/10.1038/nmeth.2598.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Mali P, Aach J, Stranges PB, Esvelt KM, Moosburner M, Kosuri S, et al. CAS9 transcriptional activators for target specificity screening and paired nickases for cooperative genome engineering. Nat Biotechnol. 2013;31(9):833–8.  https://doi.org/10.1038/nbt.2675.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature. 2016;533(7603):420–4.  https://doi.org/10.1038/nature17946.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Rees HA, Komor AC, Yeh WH, Caetano-Lopes J, Warman M, Edge ASB, et al. Improving the DNA specificity and applicability of base editing through protein engineering and protein delivery. Nat Commun. 2017;8:15790.  https://doi.org/10.1038/ncomms15790.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Liang P, Sun H, Sun Y, Zhang X, Xie X, Zhang J, et al. Effective gene editing by high-fidelity base editor 2 in mouse zygotes. Protein Cell. 2017;8(8):601–11.  https://doi.org/10.1007/s13238-017-0418-2.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH, Bryson DI, et al. Publisher correction: programmable base editing of a*T to G*C in genomic DNA without DNA cleavage. Nature. 2018;559:E8.  https://doi.org/10.1038/s41586-018-0070-x.CrossRefPubMedGoogle Scholar
  102. 102.
    Li X, Wang Y, Liu Y, Yang B, Wang X, Wei J, et al. Base editing with a Cpf1-cytidine deaminase fusion. Nat Biotechnol. 2018;36(4):324–7.  https://doi.org/10.1038/nbt.4102.CrossRefPubMedGoogle Scholar
  103. 103.
    Qu Y, Han B, Gao B, Bose S, Gong Y, Wawrowsky K, et al. Differentiation of human induced pluripotent stem cells to mammary-like organoids. Stem Cell Reports. 2017;8(2):205–15.  https://doi.org/10.1016/j.stemcr.2016.12.023.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Jamieson PR, Dekkers JF, Rios AC, Fu NY, Lindeman GJ, Visvader JE. Derivation of a robust mouse mammary organoid system for studying tissue dynamics. Development. 2017;144(6):1065–71.  https://doi.org/10.1242/dev.145045.CrossRefPubMedGoogle Scholar
  105. 105.
    Laperrousaz B, Porte S, Gerbaud S, Harma V, Kermarrec F, Hourtane V, et al. Direct transfection of clonal organoids in Matrigel microbeads: a promising approach toward organoid-based genetic screens. Nucleic Acids Res. 2018;46(12):e70.  https://doi.org/10.1093/nar/gky030.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Hennighausen L. Mouse models for breast cancer. Breast Cancer Res. 2000;2(1):2–7.CrossRefGoogle Scholar
  107. 107.
    Pittius CW, Hennighausen L, Lee E, Westphal H, Nicols E, Vitale J, et al. A milk protein gene promoter directs the expression of human tissue plasminogen activator cDNA to the mammary gland in transgenic mice. Proc Natl Acad Sci U S A. 1988;85(16):5874–8.CrossRefGoogle Scholar
  108. 108.
    Liu X, Robinson GW, Wagner KU, Garrett L, Wynshaw-Boris A, Hennighausen L. Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes Dev. 1997;11(2):179–86.CrossRefGoogle Scholar
  109. 109.
    Wagner KU, Wall RJ, St-Onge L, Gruss P, Wynshaw-Boris A, Garrett L, et al. Cre-mediated gene deletion in the mammary gland. Nucleic Acids Res. 1997;25(21):4323–30.CrossRefGoogle Scholar
  110. 110.
    Boroviak K, Doe B, Banerjee R, Yang F, Bradley A. Chromosome engineering in zygotes with CRISPR/Cas9. Genesis. 2016;54(2):78–85.  https://doi.org/10.1002/dvg.22915.CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Haapaniemi E, Botla S, Persson J, Schmierer B, Taipale J. CRISPR-Cas9 genome editing induces a p53-mediated DNA damage response. Nat Med. 2018;24:927–30.  https://doi.org/10.1038/s41591-018-0049-z.CrossRefPubMedGoogle Scholar
  112. 112.
    Ihry RJ, Worringer KA, Salick MR, Frias E, Ho D, Theriault K, et al. p53 inhibits CRISPR-Cas9 engineering in human pluripotent stem cells. Nat Med. 2018.  https://doi.org/10.1038/s41591-018-0050-6.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biological SciencesSookmyung Women’s UniversitySeoulRepublic of Korea
  2. 2.Laboratory of Genetics and Physiology, National Institutes of Diabetes, Digestive and Kidney DiseasesNational Institutes of HealthBethesdaUSA
  3. 3.BK21 Biological Science Visiting ProfessorSookmyung Women’s UniversitySeoulRepublic of Korea
  4. 4.Department of Biomedical Science and EngineeringKonkuk UniversitySeoulRepublic of Korea

Personalised recommendations