Editing the epigenome: technologies for programmable transcription and epigenetic modulation

Nature Methods

Volumn 13, Issue 2, 2016, Pages 127-137

  Thakore, Pratiksha I ^a,b   Black, Joshua B ^a,b   Hilton, Isaac B ^a,b   Gersbach, Charles A ^a,b,c  

^a Duke University   (United States)

^b DUKE UNIVERSITY   (United States)

^c DUKE UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

TRANSCRIPTION ACTIVATOR LIKE EFFECTOR NUCLEASE; ZINC FINGER PROTEIN;

CELL REPROGRAMMING TECHNIQUE; CHROMATIN STRUCTURE; CLUSTERED REGULARLY INTERSPACED SHORT PALINDROMIC REPEAT; DNA BINDING; EPIGENETICS; GENE EXPRESSION; GENE REGULATORY NETWORK; GENE REPRESSION; GENOMICS; HIGH THROUGHPUT SCREENING; HUMAN; MAMMAL CELL; NONHUMAN; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; TECHNOLOGY; TRANSCRIPTION INITIATION; TRANSCRIPTION REGULATION; ANIMAL; CRISPR CAS SYSTEM; GENE EXPRESSION REGULATION; GENETIC ENGINEERING; GENETIC EPIGENESIS; GENETIC TRANSCRIPTION; PHYSIOLOGY; PROCEDURES;

ANIMALS; CRISPR-CAS SYSTEMS; EPIGENESIS, GENETIC; EPIGENOMICS; GENE EXPRESSION REGULATION; GENETIC ENGINEERING; TRANSCRIPTION, GENETIC;

EID: 84961290066     PISSN: 15487091     EISSN: 15487105     Source Type: Journal    
DOI: 10.1038/nmeth.3733     Document Type: Review

References (164)

1. Maston, G.A., Evans, S.K. & Green, M.R. Transcriptional regulatory elements in the human genome. Annu. Rev. Genomics Hum. Genet. 7, 29-59 (2006).
2. Heintzman, N.D. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat. Genet. 39, 311-318 (2007).
3. ENCODE Project Consortium. et al. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57-74 (2012).
4. Roadmap Epigenomics Consortium. et al. Integrative analysis of 111 reference human epigenomes. Nature 518, 317-330 (2015).
5. Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934-947 (2013).
6. Ong, C.T. & Corces, V.G. Enhancer function: new insights into the regulation of tissue-specific gene expression. Nat. Rev. Genet. 12, 283-293 (2011).
7. Heintzman, N.D. et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459, 108-112 (2009).
8. Ziller, M.J. et al. Charting a dynamic DNA methylation landscape of the human genome. Nature 500, 477-481 (2013).
9. Schübeler, D. Function and information content of DNA methylation. Nature 517, 321-326 (2015).
10. Rada-Iglesias, A. et al. A unique chromatin signature uncovers early developmental enhancers in humans. Nature 470, 279-283 (2011).
11. Jin, Q. et al. Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation. EMBO J. 30, 249-262 (2011).
12. Keung, A.J., Joung, J.K., Khalil, A.S. & Collins, J.J. Chromatin regulation at the frontier of synthetic biology. Nat. Rev. Genet. 16, 159-171 (2015).
13. Klug, A. The discovery of zinc fingers and their applications in gene regulation and genome manipulation. Annu. Rev. Biochem. 79, 213-231 (2010).
14. Gersbach, C.A., Gaj, T. & Barbas, C.F. 3rd Synthetic zinc finger proteins: the advent of targeted gene regulation and genome modification technologies. Acc. Chem. Res. 47, 2309-2318 (2014).
15. Boch, J. et al. Breaking the code of DNA binDing specificity of TAL-type III effectors. Science 326, 1509-1512 (2009).
16. Moscou, M.J. & Bogdanove, A.J. A simple cipher governs DNA recognition by TAL effectors. Science 326, 1501 (2009).
17. Gasiunas, G., Barrangou, R., Horvath, P. & Siksnys, V. Cas9-crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria. Proc. Natl. Acad. Sci. USA 109, E2579-E2586 (2012).
18. Mali, P. et al. RNA-guided human genome engineering via Cas9. Science 339, 823-826 (2013).
19. Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819-823 (2013).
20. Cho, S.W., Kim, S., Kim, J.M. & Kim, J.S. Targeted genome engineering in human cells with the Cas9 RNA-guided endonuclease. Nat. Biotechnol. 31, 230-232 (2013).
21. Jinek, M. et al. RNA-programmed genome editing in human cells. Elife 2, e00471 (2013).
22. Jinek, M. et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337, 816-821 (2012).
23. Qi, L.S. et al. Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 152, 1173-1183 (2013).
24. Sternberg, S.H., Redding, S., Jinek, M., Greene, E.C. & Doudna, J.A. DNA interrogation by the CRISPR RNA-guided endonuclease Cas9. Nature 507, 62-67 (2014).
25. Pavletich, N.P. & Pabo, C.O. Zinc finger-DNA recognition: crystal structure of a Zif268-DNA complex at 2.1 Å. Science 252, 809-817 (1991).
26. Choo, Y., Sanchez-Garcia, I. & Klug, A. In vivo repression by a site-specific DNA-binDing protein designed against an oncogenic sequence. Nature 372, 642-645 (1994).
27. Liu, Q., Segal, D.J., Ghiara, J.B. & Barbas, C.F. III Design of polydactyl zinc-finger proteins for unique addressing within complex genomes. Proc. Natl. Acad. Sci. USA 94, 5525-5530 (1997).
28. Ingles, C.J., Shales, M., Cress, W.D., Triezenberg, S.J. & Greenblatt, J. Reduced binDing of TFIID to transcriptionally compromised mutants of VP16. Nature 351, 588-590 (1991).
29. Zhang, F. et al. Efficient construction of sequence-specific TAL effectors for modulating mammalian transcription. Nat. Biotechnol. 29, 149-153 (2011).
30. Beerli, R.R., Dreier, B. & Barbas, C.F. III Positive and negative regulation of endogenous genes by designed transcription factors. Proc. Natl. Acad. Sci. USA 97, 1495-1500 (2000).
31. Maeder, M.L. et al. Robust, synergistic regulation of human gene expression using TALE activators. Nat. Methods 10, 243-245 (2013).
32. Perez-Pinera, P. et al. Synergistic and tunable human gene activation by combinations of synthetic transcription factors. Nat. Methods 10, 239-242 (2013).
33. Maeder, M.L. et al. CRISPR RNA-guided activation of endogenous human genes. Nat. Methods 10, 977-979 (2013).
34. Mali, P. et al. CAS9 transcriptional activators for target specificity screening and paired nickases for cooperative genome engineering. Nat. Biotechnol. 31, 833-838 (2013).
35. Konermann, S. et al. Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex. Nature 517, 583-588 (2015).
36. Gao, X. et al. Reprogramming to pluripotency using designer TALE transcription factors targeting enhancers. Stem Cell Reports 1, 183-197 (2013).
37. Gao, X. et al. Comparison of TALE designer transcription factors and the CRISPR/dCas9 in regulation of gene expression by targeting enhancers. Nucleic Acids Res. 42, e155 (2014).
38. Hilton, I.B. et al. Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat. Biotechnol. 33, 510-517 (2015).
39. Polstein, L.R. et al. Genome-wide specificity of DNA-binding, gene regulation, and chromatin remodeling by TALE-and CRISPR/Cas9-based transcriptional activators. Genome Res. 25, 1158-1169 (2015).
40. Schmitz, M.L. & Baeuerle, P.A. The p65 subunit is responsible for the strong transcription activating potential of NF-kappa B. EMBO J. 10, 3805-3817 (1991).
41. Liu, P.Q. et al. Regulation of an endogenous locus using a panel of designed zinc finger proteins targeted to accessible chromatin regions. Activation of vascular endothelial growth factor A. J. Biol. Chem. 276, 11323-11334 (2001).
42. Ji, Q. et al. Engineered zinc-finger transcription factors activate OCT4 (POU5F1), SOX2, KLF4, c-MYC (MYC) and miR302/367. Nucleic Acids Res. 42, 6158-6167 (2014).
43. Maeder, M.L. et al. Targeted DNA demethylation and activation of endogenous genes using programmable TALE-TET1 fusion proteins. Nat. Biotechnol. 31, 1137-1142 (2013).
44. Frank, C.L. et al. Regulation of chromatin accessibility and Zic binDing at enhancers in the developing cerebellum. Nat. Neurosci. 18, 647-656 (2015).
45. Perez-Pinera, P. et al. RNA-guided gene activation by CRISPR-Cas9-based transcription factors. Nat. Methods 10, 973-976 (2013).
46. Farzadfard, F., Perli, S.D. & Lu, T.K. Tunable and multifunctional eukaryotic transcription factors based on CRISPR/Cas. ACS Synth. Biol. 2, 604-613 (2013).
47. Cheng, A.W. et al. Multiplexed activation of endogenous genes by CRISPR-on, an RNA-guided transcriptional activator system. Cell Res. 23, 1163-1171 (2013).
48. Gilbert, L.A. et al. Genome-scale CRISPR-mediated control of gene repression and activation. Cell 159, 647-661 (2014).
49. Chavez, A. et al. Highly efficient Cas9-mediated transcriptional programming. Nat. Methods 12, 326-328 (2015).
50. Chakraborty, S. et al. A CRISPR/Cas9-based system for reprogramming cell lineage specification. Stem Cell Reports 3, 940-947 (2014).
51. Tanenbaum, M.E., Gilbert, L.A., Qi, L.S., Weissman, J.S. & Vale, R.D. A protein-tagging system for signal amplification in gene expression and fluorescence imaging. Cell 159, 635-646 (2014).
52. Staudt, M.R. & Dittmer, D.P. The Rta/Orf50 transactivator proteins of the gamma-herpesviridae. Curr. Top. Microbiol. Immunol. 312, 71-100 (2007).
53. Grimm, D. et al. Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 441, 537-541 (2006).
54. Gregory, D.J., Zhang, Y., Kobzik, L. & Fedulov, A.V. Specific transcriptional enhancement of inducible nitric oxide synthase by targeted promoter demethylation. Epigenetics 8, 1205-1212 (2013).
55. Chen, H. et al. Induced DNA demethylation by targeting Ten-Eleven Translocation 2 to the human ICAM-1 promoter. Nucleic Acids Res. 42, 1563-1574 (2014).
56. Li, K. et al. Manipulation of prostate cancer metastasis by locus-specific modification of the CRMP4 promoter region using chimeric TALE DNA methyltransferase and demethylase. Oncotarget 6, 10030-10044 (2015).
57. Jackson, A.L. et al. Widespread siRNA off-target transcript silencing mediated by seed region sequence complementarity. RNA 12, 1179-1187 (2006).
58. Shalem, O., Sanjana, N.E. & Zhang, F. High-throughput functional genomics using CRISPR-Cas9. Nat. Rev. Genet. 16, 299-311 (2015).
59. Li, Y. et al. Modular construction of mammalian gene circuits using TALE transcriptional repressors. Nat. Chem. Biol. 11, 207-213 (2015).
60. Larson, M.H. et al. CRISPR interference (CRISPRi) for sequence-specific control of gene expression. Nat. Protoc. 8, 2180-2196 (2013).
61. Garriga-Canut, M. et al. Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6/2 mice. Proc. Natl. Acad. Sci. USA 109, E3136-E3145 (2012).
62. Gilbert, L.A. et al. CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell 154, 442-451 (2013).
63. Snowden, A.W., Gregory, P.D., Case, C.C. & Pabo, C.O. Gene-specific targeting of H3K9 methylation is sufficient for initiating repression in vivo. Curr. Biol. 12, 2159-2166 (2002).
64. Kearns, N.A. et al. Functional annotation of native enhancers with a Cas9-histone demethylase fusion. Nat. Methods 12, 401-403 (2015).
65. Beerli, R.R., Segal, D.J., Dreier, B. & Barbas, C.F. III Toward controlling gene expression at will: specific regulation of the erbB-2/HER-2 promoter by using polydactyl zinc finger proteins constructed from modular builDing blocks. Proc. Natl. Acad. Sci. USA 95, 14628-14633 (1998).
66. Cong, L., Zhou, R., Kuo, Y.C., Cunniff, M. & Zhang, F. Comprehensive interrogation of natural TALE DNA-binDing modules and transcriptional repressor domains. Nat. Commun. 3, 968 (2012).
67. Sripathy, S.P., Stevens, J. & Schultz, D.C. The KAP1 corepressor functions to coordinate the assembly of de novo HP1-demarcated microenvironments of heterochromatin required for KRAB zinc finger protein-mediated transcriptional repression. Mol. Cell. Biol. 26, 8623-8638 (2006).
68. Groner, A.C. et al. KRAB-zinc finger proteins and KAP1 can mediate long-range transcriptional repression through heterochromatin spreading. PLoS Genet. 6, e1000869 (2010).
69. Schultz, D.C., Ayyanathan, K., Negorev, D., Maul, G.G. & Rauscher, F.J. 3rd SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes Dev. 16, 919-932 (2002).
70. Reynolds, N. et al. NuRD-mediated deacetylation of H3K27 facilitates recruitment of Polycomb Repressive Complex 2 to direct gene repression. EMBO J. 31, 593-605 (2012).
71. Thakore, P.I. et al. Highly specific epigenome editing by CRISPR-Cas9 repressors for silencing of distal regulatory elements. Nat. Methods 12, 1143-1149 (2015).
72. David, G. et al. Specific requirement of the chromatin modifier mSin3B in cell cycle exit and cellular differentiation. Proc. Natl. Acad. Sci. USA 105, 4168-4172 (2008).
73. Rivenbark, A.G. et al. Epigenetic reprogramming of cancer cells via targeted DNA methylation. Epigenetics 7, 350-360 (2012).
74. Stolzenburg, S. et al. Targeted silencing of the oncogenic transcription factor SOX2 in breast cancer. Nucleic Acids Res. 40, 6725-6740 (2012).
75. Siddique, A.N. et al. Targeted methylation and gene silencing of VEGF-A in human cells by using a designed Dnmt3a-Dnmt3L single-chain fusion protein with increased DNA methylation activity. J. Mol. Biol. 425, 479-491 (2013).
76. Stolzenburg, S. et al. Stable oncogenic silencing in vivo by programmable and targeted de novo DNA methylation in breast cancer. Oncogene 34, 5427-5435 (2015).
77. Mendenhall, E.M. et al. Locus-specific editing of histone modifications at endogenous enhancers. Nat. Biotechnol. 31, 1133-1136 (2013).
78. Konermann, S. et al. Optical control of mammalian endogenous transcription and epigenetic states. Nature 500, 472-476 (2013).
79. Heller, E.A. et al. Locus-specific epigenetic remodeling controls addiction-and depression-related behaviors. Nat. Neurosci. 17, 1720-1727 (2014).
80. Kungulovski, G. et al. Targeted epigenome editing of an endogenous locus with chromatin modifiers is not stably maintained. Epigenetics Chromatin 8, 12 (2015).
81. Hathaway, N.A. et al. Dynamics and memory of heterochromatin in living cells. Cell 149, 1447-1460 (2012).
82. Ayyanathan, K. et al. Regulated recruitment of HP1 to a euchromatic gene induces mitotically heritable, epigenetic gene silencing: a mammalian cell culture model of gene variegation. Genes Dev. 17, 1855-1869 (2003).
83. Bhaumik, S.R., Smith, E. & Shilatifard, A. Covalent modifications of histones during development and disease pathogenesis. Nat. Struct. Mol. Biol. 14, 1008-1016 (2007).
84. Grimmer, M.R. et al. Analysis of an artificial zinc finger epigenetic modulator: widespread binDing but limited regulation. Nucleic Acids Res. 42, 10856-10868 (2014).
85. Wu, X. et al. Genome-wide binDing of the CRISPR endonuclease Cas9 in mammalian cells. Nat. Biotechnol. 32, 670-676 (2014).
86. Kuscu, C., Arslan, S., Singh, R., Thorpe, J. & Adli, M. Genome-wide analysis reveals characteristics of off-target sites bound by the Cas9 endonuclease. Nat. Biotechnol. 32, 677-683 (2014).
87. O'Geen, H., Henry, I.M., Bhakta, M.S., Meckler, J.F. & Segal, D.J. A genome-wide analysis of Cas9 binDing specificity using ChIP-seq and targeted sequence capture. Nucleic Acids Res. 43, 3389-3404 (2015).
88. Duan, J. et al. Genome-wide identification of CRISPR/Cas9 off-targets in human genome. Cell Res. 24, 1009-1012 (2014).
89. Tan, S. et al. Zinc-finger protein-targeted gene regulation: genomewide single-gene specificity. Proc. Natl. Acad. Sci. USA 100, 11997-12002 (2003).
90. Bolukbasi, M.F., Gupta, A. & Wolfe, S.A. Creating and evaluating accurate CRISPR-Cas9 scalpels for genomic surgery. Nat. Methods 13, 41-50 (2016).
91. Hsu, P.D. et al. DNA targeting specificity of RNA-guided Cas9 nucleases. Nat. Biotechnol. 31, 827-832 (2013).
92. Fu, Y., Sander, J.D., Reyon, D., Cascio, V.M. & Joung, J.K. Improving CRISPR-Cas nuclease specificity using truncated guide RNAs. Nat. Biotechnol. 32, 279-284 (2014).
93. Zetsche, B., Volz, S.E. & Zhang, F. A split-Cas9 architecture for inducible genome editing and transcription modulation. Nat. Biotechnol. 33, 139-142 (2015).
94. Aach, J., Mali, P. & Church, G.M. CasFinder: flexible algorithm for identifying specific Cas9 targets in genomes. bioRxiv doi:10.1101/005074 (12 May 2014).
95. Heigwer, F., Kerr, G. & Boutros, M. E-CRISP: fast CRISPR target site identification. Nat. Methods 11, 122-123 (2014).
96. Doench, J.G. et al. Rational design of highly active sgRNAs for CRISPR-Cas9-mediated gene inactivation. Nat. Biotechnol. 32, 1262-1267 (2014).
97. Singh, R., Kuscu, C., Quinlan, A., Qi, Y. & Adli, M. Cas9-chromatin binDing information enables more accurate CRISPR off-target prediction. Nucleic Acids Res. 43, e118 (2015).
98. Zalatan, J.G. et al. Engineering complex synthetic transcriptional programs with CRISPR RNA scaffolds. Cell 160, 339-350 (2015).
99. Mercer, A.C., Gaj, T., Sirk, S.J., Lamb, B.M. & Barbas, C.F. III Regulation of endogenous human gene expression by ligand-inducible TALE transcription factors. ACS Synth. Biol. 3, 723-730 (2014).
100. Nissim, L., Perli, S.D., Fridkin, A., Perez-Pinera, P. & Lu, T.K. Multiplexed and programmable regulation of gene networks with an integrated RNA and CRISPR/Cas toolkit in human cells. Mol. Cell 54, 698-710 (2014).
101. Tsai, S.Q. et al. Dimeric CRISPR RNA-guided FokI nucleases for highly specific genome editing. Nat. Biotechnol. 32, 569-576 (2014).
102. Kennedy, M.J. et al. Rapid blue-light-mediated induction of protein interactions in living cells. Nat. Methods 7, 973-975 (2010).
103. Polstein, L.R. & Gersbach, C.A. Light-inducible spatiotemporal control of gene activation by customizable zinc finger transcription factors. J. Am. Chem. Soc. 134, 16480-16483 (2012).
104. Nihongaki, Y., Yamamoto, S., Kawano, F., Suzuki, H. & Sato, M. CRISPR-Cas9-based photoactivatable transcription system. Chem. Biol. 22, 169-174 (2015).
105. Polstein, L.R. & Gersbach, C.A. A light-inducible CRISPR-Cas9 system for control of endogenous gene activation. Nat. Chem. Biol. 11, 198-200 (2015).
106. Hilton, I.B. & Gersbach, C.A. Enabling functional genomics with genome engineering. Genome Res. 25, 1442-1455 (2015).
107. Crocker, J. & Stern, D.L. TALE-mediated modulation of transcriptional enhancers in vivo. Nat. Methods 10, 762-767 (2013).
108. Deng, W. et al. Reactivation of developmentally silenced globin genes by forced chromatin looping. Cell 158, 849-860 (2014).
109. Phillips, J.E. & Corces, V.G. CTCF: master weaver of the genome. Cell 137, 1194-1211 (2009).
110. Khalil, A.S. et al. A synthetic biology framework for programming eukaryotic transcription functions. Cell 150, 647-658 (2012).
111. Kiani, S. et al. CRISPR transcriptional repression devices and layered circuits in mammalian cells. Nat. Methods 11, 723-726 (2014).
112. Lienert, F. et al. Two-and three-input TALE-based AND logic computation in embryonic stem cells. Nucleic Acids Res. 41, 9967-9975 (2013).
113. Keung, A.J., Bashor, C.J., Kiriakov, S., Collins, J.J. & Khalil, A.S. Using targeted chromatin regulators to engineer combinatorial and spatial transcriptional regulation. Cell 158, 110-120 (2014).
114. Esvelt, K.M. et al. Orthogonal Cas9 proteins for RNA-guided gene regulation and editing. Nat. Methods 10, 1116-1121 (2013).
115. Ran, F.A. et al. In vivo genome editing using Staphylococcus aureus Cas9. Nature 520, 186-191 (2015).
116. Hou, Z. et al. Efficient genome engineering in human pluripotent stem cells using Cas9 from Neisseria meningitidis. Proc. Natl. Acad. Sci. USA 110, 15644-15649 (2013).
117. Kleinstiver, B.P. et al. Engineered CRISPR-Cas9 nucleases with altered PAM specificities. Nature 523, 481-485 (2015).
118. Briner, A.E. et al. Guide RNA functional modules direct Cas9 activity and orthogonality. Mol. Cell 56, 333-339 (2014).
119. Shechner, D.M., Hacisuleyman, E., Younger, S.T. & Rinn, J.L. Multiplexable, locus-specific targeting of long RNAs with CRISPR-Display. Nat. Methods 12, 664-670 (2015).
120. Dahlman, J.E. et al. Orthogonal gene knockout and activation with a catalytically active Cas9 nuclease. Nat. Biotechnol. 33, 1159-1161 (2015).
121. Kiani, S. et al. Cas9 gRNA engineering for genome editing, activation and repression. Nat. Methods 12, 1051-1054 (2015).
122. Josephs, E.A. et al. Structure and specificity of the RNA-guided endonuclease Cas9 during DNA interrogation, target binDing and cleavage. Nucleic Acids Res. 43, 8924-8941 (2015).
123. Blancafort, P., Magnenat, L. & Barbas, C.F. III Scanning the human genome with combinatorial transcription factor libraries. Nat. Biotechnol. 21, 269-274 (2003).
124. Park, K.S. et al. Phenotypic alteration of eukaryotic cells using randomized libraries of artificial transcription factors. Nat. Biotechnol. 21, 1208-1214 (2003).
125. Graf, T. & Enver, T. Forcing cells to change lineages. Nature 462, 587-594 (2009).
126. Vierbuchen, T. & Wernig, M. Direct lineage conversions: unnatural but useful? Nat. Biotechnol. 29, 892-907 (2011).
127. Hanna, J. et al. Direct cell reprogramming is a stochastic process amenable to acceleration. Nature 462, 595-601 (2009).
128. Wapinski, O.L. et al. Hierarchical mechanisms for direct reprogramming of fibroblasts to neurons. Cell 155, 621-635 (2013).
129. Kim, K. et al. Epigenetic memory in induced pluripotent stem cells. Nature 467, 285-290 (2010).
130. Lister, R. et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471, 68-73 (2011).
131. Kelly, T.K., De Carvalho, D.D. & Jones, P.A. Epigenetic modifications as therapeutic targets. Nat. Biotechnol. 28, 1069-1078 (2010).
132. Gräslund, T., Li, X., Magnenat, L., Popkov, M. & Barbas, C.F. III Exploring strategies for the design of artificial transcription factors: targeting sites proximal to known regulatory regions for the induction of gamma-globin expression and the treatment of sickle cell disease. J. Biol. Chem. 280, 3707-3714 (2005).
133. Wilber, A. et al. A zinc-finger transcriptional activator designed to interact with the gamma-globin gene promoters enhances fetal hemoglobin production in primary human adult erythroblasts. Blood 115, 3033-3041 (2010).
134. Laganiere, J. et al. An engineered zinc finger protein activator of the endogenous glial cell line-derived neurotrophic factor gene provides functional neuroprotection in a rat model of Parkinson's disease. J. Neurosci. 30, 16469-16474 (2010).
135. Rebar, E.J. et al. Induction of angiogenesis in a mouse model using engineered transcription factors. Nat. Med. 8, 1427-1432 (2002).
136. Dai, Q. et al. Engineered zinc finger-activating vascular endothelial growth factor transcription factor plasmid DNA induces therapeutic angiogenesis in rabbits with hindlimb ischemia. Circulation 110, 2467-2475 (2004).
137. Yokoi, K. et al. Gene transfer of an engineered zinc finger protein enhances the anti-angiogenic defense system. Mol. Ther. 15, 1917-1923 (2007).
138. Chapdelaine, P., Coulombe, Z., Chikh, A., Gerard, C. & Tremblay, J.P. A potential new therapeutic approach for Friedreich ataxia: induction of frataxin expression with TALE proteins. Mol. Ther. Nucleic Acids 2, e119 (2013).
139. Magnenat, L., Schwimmer, L.J. & Barbas, C.F. III Drug-inducible and simultaneous regulation of endogenous genes by single-chain nuclear receptor-based zinc-finger transcription factor gene switches. Gene Ther. 15, 1223-1232 (2008).
140. Himeda, C.L., Jones, T.I. & Jones, P.L. CRISPR/dCas9-mediated transcriptional inhibition ameliorates the epigenetic dysregulation at D4Z4 and represses DUX4-fl in FSH muscular dystrophy. Mol. Ther. doi:10.1038/mt.2015.200 (3 November 2015).
141. Jakovcevski, M. & Akbarian, S. Epigenetic mechanisms in neurological disease. Nat. Med. 18, 1194-1204 (2012).
142. Fierz, B. & Muir, T.W. Chromatin as an expansive canvas for chemical biology. Nat. Chem. Biol. 8, 417-427 (2012).
143. Azad, N., Zahnow, C.A., Rudin, C.M. & Baylin, S.B. The future of epigenetic therapy in solid tumours-lessons from the past. Nat. Rev. Clin. Oncol. 10, 256-266 (2013).
144. Kay, M.A. State-of-the-art gene-based therapies: the road ahead. Nat. Rev. Genet. 12, 316-328 (2011).
145. Burnett, J.C. & Rossi, J.J. RNA-based therapeutics: current progress and future prospects. Chem. Biol. 19, 60-71 (2012).
146. Hendel, A. et al. Chemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells. Nat. Biotechnol. 33, 985-989 (2015).
147. Bernstein, B.E. et al. Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 120, 169-181 (2005).
148. Wang, Z. et al. Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell 138, 1019-1031 (2009).
149. Wang, F., Marshall, C.B. & Ikura, M. Transcriptional/epigenetic regulator CBP/p300 in tumorigenesis: structural and functional versatility in target recognition. Cell. Mol. Life Sci. 70, 3989-4008 (2013).
150. Dou, Y. et al. Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nat. Struct. Mol. Biol. 13, 713-719 (2006).
151. Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941-953 (2004).
152. Agger, K. et al. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature 449, 731-734 (2007).
153. Bernstein, B.E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315-326 (2006).
154. Di Croce, L. & Helin, K. Transcriptional regulation by Polycomb group proteins. Nat. Struct. Mol. Biol. 20, 1147-1155 (2013).
155. Cao, R. et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 1039-1043 (2002).
156. Peters, A.H. et al. Partitioning and plasticity of repressive histone methylation states in mammalian chromatin. Mol. Cell 12, 1577-1589 (2003).
157. Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593-599 (2000).
158. Tachibana, M. et al. G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev. 16, 1779-1791 (2002).
159. Baubec, T. et al. Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature 520, 243-247 (2015).
160. Chen, T., Ueda, Y., Dodge, J.E., Wang, Z. & Li, E. Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b. Mol. Cell. Biol. 23, 5594-5605 (2003).
161. Liao, J. et al. Targeted disruption of DNMT1, DNMT3A and DNMT3B in human embryonic stem cells. Nat. Genet. 47, 469-478 (2015).
162. Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930-935 (2009).
163. He, Y.F. et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303-1307 (2011).
164. Bernstein, D.L., Le Lay, J.E., Ruano, E.G. & Kaestner, K.H. TALE-mediated epigenetic suppression of CDKN2A increases replication in human fibroblasts. J. Clin. Invest. 125, 1998-2006 (2015).