Multiplex Enhancer Interference Reveals Collaborative Control of Gene Regulation by Estrogen Receptor α-Bound Enhancers

Cell Systems

Volumn 5, Issue 4, 2017, Pages 333-344.e5

  Carleton, Julia B ^a   Berrett, Kristofer C ^a   Gertz, Jason ^a  

^a UNIVERSITY OF UTAH SCHOOL OF MEDICINE   (United States)

Author keywords

CRISPR Cas9; enhancer; enhancer interference; estrogen receptor alpha; gene regulation

Indexed keywords

ESTRADIOL; ESTROGEN RECEPTOR ALPHA; HISTONE DEACETYLASE; TRANSCRIPTION FACTOR; ESTROGEN RECEPTOR ALPHA, HUMAN; PROTEIN BINDING;

ARTICLE; BINDING SITE; CLUSTERED REGULARLY INTERSPACED SHORT PALINDROMIC REPEAT; ENHANCER REGION; ESTROGEN RESPONSIVE ELEMENT; GENE CLUSTER; GENE EXPRESSION REGULATION; GENE LOCUS; GENOMICS; ISHIKAWA CELL LINE; MATHEMATICAL MODEL; PRIORITY JOURNAL; TRANSCRIPTION REGULATION; UPREGULATION; CELL LINE; GENETIC TRANSCRIPTION; GENETICS; HUMAN; PROMOTER REGION;

CELL LINE; CLUSTERED REGULARLY INTERSPACED SHORT PALINDROMIC REPEATS; ENHANCER ELEMENTS, GENETIC; ESTROGEN RECEPTOR ALPHA; GENE EXPRESSION REGULATION; HUMANS; PROMOTER REGIONS, GENETIC; PROTEIN BINDING; TRANSCRIPTION FACTORS; TRANSCRIPTION, GENETIC;

EID: 85030178360     PISSN: 24054712     EISSN: 24054720     Source Type: Journal    
DOI: 10.1016/j.cels.2017.08.011     Document Type: Article

References (68)

1. Alland, L., Muhle, R., Hou, H. Jr., Potes, J., Chin, L., Schreiber-Agus, N., DePinho, R.A., Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression. Nature 387 (1997), 49–55.
2. Anders, S., Pyl, P.T., Huber, W., HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics 31 (2015), 166–169.
3. Andersson, R., Gebhard, C., Miguel-Escalada, I., Hoof, I., Bornholdt, J., Boyd, M., Chen, Y., Zhao, X., Schmidl, C., Suzuki, T., et al. An atlas of active enhancers across human cell types and tissues. Nature 507 (2014), 455–461.
4. Ayer, D.E., Laherty, C.D., Lawrence, Q.A., Armstrong, A.P., Eisenman, R.N., Mad proteins contain a dominant transcription repression domain. Mol. Cell. Biol. 16 (1996), 5772–5781.
5. Banerji, J., Rusconi, S., Schaffner, W., Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences. Cell 27 (1981), 299–308.
6. Banerji, J., Olson, L., Schaffner, W., A lymphocyte-specific cellular enhancer is located downstream of the joining region in immunoglobulin heavy chain genes. Cell 33 (1983), 729–740.
7. Barolo, S., Shadow enhancers: frequently asked questions about distributed cis-regulatory information and enhancer redundancy. Bioessays 34 (2012), 135–141.
8. Bender, M.A., Ragoczy, T., Lee, J., Byron, R., Telling, A., Dean, A., Groudine, M., The hypersensitive sites of the murine beta-globin locus control region act independently to affect nuclear localization and transcriptional elongation. Blood 119 (2012), 3820–3827.
9. Blasquez, V.C., Hale, M.A., Trevorrow, K.W., Garrard, W.T., Immunoglobulin kappa gene enhancers synergistically activate gene expression but independently determine chromatin structure. J. Biol. Chem. 267 (1992), 23888–23893.
10. Cannavo, E., Khoueiry, P., Garfield, D.A., Geeleher, P., Zichner, T., Gustafson, E.H., Ciglar, L., Korbel, J.O., Furlong, E.E., Shadow enhancers are pervasive features of developmental regulatory networks. Curr. Biol. 26 (2016), 38–51.
11. Cheng, Y., Wu, W., Kumar, S.A., Yu, D., Deng, W., Tripic, T., King, D.C., Chen, K.B., Zhang, Y., Drautz, D., et al. Erythroid GATA1 function revealed by genome-wide analysis of transcription factor occupancy, histone modifications, and mRNA expression. Genome Res. 19 (2009), 2172–2184.
12. Cheng, A.W., Wang, H., Yang, H., Shi, L., Katz, Y., Theunissen, T.W., Rangarajan, S., Shivalila, C.S., Dadon, D.B., Jaenisch, R., Multiplexed activation of endogenous genes by CRISPR-on, an RNA-guided transcriptional activator system. Cell Res. 23 (2013), 1163–1171.
13. Cooper, G.M., Stone, E.A., Asimenos, G., Program, N.C.S., Green, E.D., Batzoglou, S., Sidow, A., Distribution and intensity of constraint in mammalian genomic sequence. Genome Res 15 (2005), 901–913.
14. de Villiers, J., Schaffner, W., A small segment of polyoma virus DNA enhances the expression of a cloned beta-globin gene over a distance of 1400 base pairs. Nucleic Acids Res. 9 (1981), 6251–6264.
15. Droog, M., Mensink, M., Zwart, W., The estrogen receptor alpha-cistrome beyond breast cancer. Mol. Endocrinol. 30 (2016), 1046–1058.
16. Dukler, N., Gulko, B., Huang, Y.F., Siepel, A., Is a super-enhancer greater than the sum of its parts?. Nat. Genet. 49 (2016), 2–3.
17. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489 (2012), 57–74.
18. Fujioka, M., Emi-Sarker, Y., Yusibova, G.L., Goto, T., Jaynes, J.B., Analysis of an even-skipped rescue transgene reveals both composite and discrete neuronal and early blastoderm enhancers, and multi-stripe positioning by gap gene repressor gradients. Development 126 (1999), 2527–2538.
19. Fulco, C.P., Munschauer, M., Anyoha, R., Munson, G., Grossman, S.R., Perez, E.M., Kane, M., Cleary, B., Lander, E.S., Engreitz, J.M., Systematic mapping of functional enhancer-promoter connections with CRISPR interference. Science 354 (2016), 769–773.
20. Fullwood, M.J., Liu, M.H., Pan, Y.F., Liu, J., Xu, H., Mohamed, Y.B., Orlov, Y.L., Velkov, S., Ho, A., Mei, P.H., et al. An oestrogen-receptor-alpha-bound human chromatin interactome. Nature 462 (2009), 58–64.
21. Fulton, R., van Ness, B., Selective synergy of immunoglobulin enhancer elements in B-cell development: a characteristic of kappa light chain enhancers, but not heavy chain enhancers. Nucleic Acids Res. 22 (1994), 4216–4223.
22. Gertz, J., Reddy, T.E., Varley, K.E., Garabedian, M.J., Myers, R.M., Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 22 (2012), 2153–2162.
23. Gertz, J., Savic, D., Varley, K.E., Partridge, E.C., Safi, A., Jain, P., Cooper, G.M., Reddy, T.E., Crawford, G.E., Myers, R.M., Distinct properties of cell-type-specific and shared transcription factor binding sites. Mol. Cell 52 (2013), 25–36.
24. Gilbert, L.A., Larson, M.H., Morsut, L., Liu, Z., Brar, G.A., Torres, S.E., Stern-Ginossar, N., Brandman, O., Whitehead, E.H., Doudna, J.A., et al. CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell 154 (2013), 442–451.
25. Groner, A.C., Meylan, S., Ciuffi, A., Zangger, N., Ambrosini, G., Denervaud, N., Bucher, P., Trono, D., KRAB-zinc finger proteins and KAP1 can mediate long-range transcriptional repression through heterochromatin spreading. PLoS Genet., 6, 2010, e1000869.
26. Guo, Y., Monahan, K., Wu, H., Gertz, J., Varley, K.E., Li, W., Myers, R.M., Maniatis, T., Wu, Q., CTCF/cohesin-mediated DNA looping is required for protocadherin alpha promoter choice. Proc. Natl. Acad. Sci. USA 109 (2012), 21081–21086.
27. Hay, D., Hughes, J.R., Babbs, C., Davies, J.O., Graham, B.J., Hanssen, L.L., Kassouf, M.T., Oudelaar, A.M., Sharpe, J.A., Suciu, M.C., et al. Genetic dissection of the alpha-globin super-enhancer in vivo. Nat. Genet. 48 (2016), 895–903.
28. Heigwer, F., Kerr, G., Boutros, M., E-CRISP: fast CRISPR target site identification. Nat. Methods 11 (2014), 122–123.
29. Hertz, G.Z., Stormo, G.D., Identifying DNA and protein patterns with statistically significant alignments of multiple sequences. Bioinformatics 15 (1999), 563–577.
30. Hilton, I.B., D'Ippolito, A.M., Vockley, C.M., Thakore, P.I., Crawford, G.E., Reddy, T.E., Gersbach, C.A., Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat. Biotechnol. 33 (2015), 510–517.
31. Hong, J.W., Hendrix, D.A., Levine, M.S., Shadow enhancers as a source of evolutionary novelty. Science, 321, 2008, 1314.
32. Joo, J.Y., Schaukowitch, K., Farbiak, L., Kilaru, G., Kim, T.K., Stimulus-specific combinatorial functionality of neuronal c-fos enhancers. Nat. Neurosci. 19 (2016), 75–83.
33. Kearns, N.A., Pham, H., Tabak, B., Genga, R.M., Silverstein, N.J., Garber, M., Maehr, R., Functional annotation of native enhancers with a Cas9-histone demethylase fusion. Nat. Methods 12 (2015), 401–403.
34. Kehayova, P., Monahan, K., Chen, W., Maniatis, T., Regulatory elements required for the activation and repression of the protocadherin-alpha gene cluster. Proc. Natl. Acad. Sci. USA 108 (2011), 17195–17200.
35. Kim, T.K., Hemberg, M., Gray, J.M., Costa, A.M., Bear, D.M., Wu, J., Harmin, D.A., Laptewicz, M., Barbara-Haley, K., Kuersten, S., et al. Widespread transcription at neuronal activity-regulated enhancers. Nature 465 (2010), 182–187.
36. Kim, D., Langmead, B., Salzberg, S.L., HISAT: a fast spliced aligner with low memory requirements. Nat. Methods 12 (2015), 357–360.
37. Konermann, S., Brigham, M.D., Trevino, A.E., Joung, J., Abudayyeh, O.O., Barcena, C., Hsu, P.D., Habib, N., Gootenberg, J.S., Nishimasu, H., et al. Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex. Nature 517 (2015), 583–588.
38. Lam, D.D., de Souza, F.S., Nasif, S., Yamashita, M., Lopez-Leal, R., Otero-Corchon, V., Meece, K., Sampath, H., Mercer, A.J., Wardlaw, S.L., et al. Partially redundant enhancers cooperatively maintain mammalian Pomc expression above a critical functional threshold. PLoS Genet., 11, 2015, e1004935.
39. Langmead, B., Trapnell, C., Pop, M., Salzberg, S.L., Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol., 10, 2009, R25.
40. Larson, M.H., Gilbert, L.A., Wang, X., Lim, W.A., Weissman, J.S., Qi, L.S., CRISPR interference (CRISPRi) for sequence-specific control of gene expression. Nat. Protoc. 8 (2013), 2180–2196.
41. Leddin, M., Perrod, C., Hoogenkamp, M., Ghani, S., Assi, S., Heinz, S., Wilson, N.K., Follows, G., Schonheit, J., Vockentanz, L., et al. Two distinct auto-regulatory loops operate at the PU.1 locus in B cells and myeloid cells. Blood 117 (2011), 2827–2838.
42. Love, M.I., Huber, W., Anders, S., Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol., 15, 2014, 550.
43. Mali, P., Yang, L., Esvelt, K.M., Aach, J., Guell, M., DiCarlo, J.E., Norville, J.E., Church, G.M., RNA-guided human genome engineering via Cas9. Science 339 (2013), 823–826.
44. Montavon, T., Soshnikova, N., Mascrez, B., Joye, E., Thevenet, L., Splinter, E., de Laat, W., Spitz, F., Duboule, D., A regulatory archipelago controls Hox genes transcription in digits. Cell 147 (2011), 1132–1145.
45. Nechaev, S., Fargo, D.C., dos Santos, G., Liu, L., Gao, Y., Adelman, K., Global analysis of short RNAs reveals widespread promoter-proximal stalling and arrest of Pol II in Drosophila. Science 327 (2010), 335–338.
46. Perez-Pinera, P., Kocak, D.D., Vockley, C.M., Adler, A.F., Kabadi, A.M., Polstein, L.R., Thakore, P.I., Glass, K.A., Ousterout, D.G., Leong, K.W., et al. RNA-guided gene activation by CRISPR-Cas9-based transcription factors. Nat. Methods 10 (2013), 973–976.
47. Perry, M.W., Boettiger, A.N., Bothma, J.P., Levine, M., Shadow enhancers foster robustness of Drosophila gastrulation. Curr. Biol. 20 (2010), 1562–1567.
48. Perry, M.W., Boettiger, A.N., Levine, M., Multiple enhancers ensure precision of gap gene-expression patterns in the Drosophila embryo. Proc. Natl. Acad. Sci. USA 108 (2011), 13570–13575.
49. Qi, L.S., Larson, M.H., Gilbert, L.A., Doudna, J.A., Weissman, J.S., Arkin, A.P., Lim, W.A., Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 152 (2013), 1173–1183.
50. Quinlan, A.R., Hall, I.M., BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26 (2010), 841–842.
51. Ran, F.A., Hsu, P.D., Wright, J., Agarwala, V., Scott, D.A., Zhang, F., Genome engineering using the CRISPR-Cas9 system. Nat. Protoc. 8 (2013), 2281–2308.
52. Reddy, T.E., Pauli, F., Sprouse, R.O., Neff, N.F., Newberry, K.M., Garabedian, M.J., Myers, R.M., Genomic determination of the glucocorticoid response reveals unexpected mechanisms of gene regulation. Genome Res. 19 (2009), 2163–2171.
53. Rennoll, S.A., Scott, S.A., Yochum, G.S., Targeted repression of AXIN2 and MYC gene expression using designer TALEs. Biochem. Biophys. Res. Commun. 446 (2014), 1120–1125.
54. Roadmap Epigenomics, C., Kundaje, A., Meuleman, W., Ernst, J., Bilenky, M., Yen, A., Heravi-Moussavi, A., Kheradpour, P., Zhang, Z., Wang, J., et al. Integrative analysis of 111 reference human epigenomes. Nature 518 (2015), 317–330.
55. Santos, G.M., Fairall, L., Schwabe, J.W., Negative regulation by nuclear receptors: a plethora of mechanisms. Trends Endocrinol. Metab. 22 (2011), 87–93.
56. Savic, D., Roberts, B.S., Carleton, J.B., Partridge, E.C., White, M.A., Cohen, B.A., Cooper, G.M., Gertz, J., Myers, R.M., Promoter-distal RNA polymerase II binding discriminates active from inactive CCAAT/enhancer-binding protein beta binding sites. Genome Res. 25 (2015), 1791–1800.
57. Shen, B., Zhang, W., Zhang, J., Zhou, J., Wang, J., Chen, L., Wang, L., Hodgkins, A., Iyer, V., Huang, X., et al. Efficient genome modification by CRISPR-Cas9 nickase with minimal off-target effects. Nat. Methods 11 (2014), 399–402.
58. Shin, H.Y., Willi, M., Yoo, K.H., Zeng, X., Wang, C., Metser, G., Hennighausen, L., Hierarchy within the mammary STAT5-driven Wap super-enhancer. Nat. Genet. 48 (2016), 904–911.
59. Small, S., Blair, A., Levine, M., Regulation of even-skipped stripe 2 in the Drosophila embryo. EMBO J. 11 (1992), 4047–4057.
60. Stern, D.L., Frankel, N., The structure and evolution of cis-regulatory regions: the shavenbaby story. Philos. Trans. R. Soc. Lond. B Biol. Sci., 368, 2013, 20130028.
61. Stine, Z.E., McGaughey, D.M., Bessling, S.L., Li, S., McCallion, A.S., Steroid hormone modulation of RET through two estrogen responsive enhancers in breast cancer. Hum. Mol. Genet. 20 (2011), 3746–3756.
62. Thakore, P.I., D'Ippolito, A.M., Song, L., Safi, A., Shivakumar, N.K., Kabadi, A.M., Reddy, T.E., Crawford, G.E., Gersbach, C.A., Highly specific epigenome editing by CRISPR-Cas9 repressors for silencing of distal regulatory elements. Nat. Methods 12 (2015), 1143–1149.
63. Vockley, C.M., D'Ippolito, A.M., McDowell, I.C., Majoros, W.H., Safi, A., Song, L., Crawford, G.E., Reddy, T.E., Direct GR binding sites potentiate clusters of TF binding across the human genome. Cell 166 (2016), 1269–1281.e19.
64. Wang, Z., Zang, C., Rosenfeld, J.A., Schones, D.E., Barski, A., Cuddapah, S., Cui, K., Roh, T.Y., Peng, W., Zhang, M.Q., et al. Combinatorial patterns of histone acetylations and methylations in the human genome. Nat. Genet. 40 (2008), 897–903.
65. Xie, S., Duan, J., Li, B., Zhou, P., Hon, G.C., Multiplexed engineering and analysis of combinatorial enhancer activity in single cells. Mol. Cell 66 (2017), 285–299.e5.
66. Xu, H., Xiao, T., Chen, C.H., Li, W., Meyer, C.A., Wu, Q., Wu, D., Cong, L., Zhang, F., Liu, J.S., et al. Sequence determinants of improved CRISPR sgRNA design. Genome Res. 25 (2015), 1147–1157.
67. Yuh, C.H., Davidson, E.H., Modular cis-regulatory organization of Endo16, a gut-specific gene of the sea urchin embryo. Development 122 (1996), 1069–1082.
68. Zhang, Y., Liu, T., Meyer, C.A., Eeckhoute, J., Johnson, D.S., Bernstein, B.E., Nusbaum, C., Myers, R.M., Brown, M., Li, W., et al. Model-based analysis of ChIP-seq (MACS). Genome Biol., 9, 2008, R137.