Enhancer reprogramming in tumor progression: a new route towards cancer cell plasticity

Cellular and Molecular Life Sciences

Volumn 75, Issue 14, 2018, Pages 2537-2555

  Fagnocchi, Luca ^a   Poli, Vittoria ^a   Zippo, Alessio ^a,b,c  

^a UNIVERSITY OF TRENTO   (Italy)

^b Istituto Nazionale di Genetica Molecolare   (Italy)

^c FONDAZIONE IRCCS CA GRANDA OSPEDALE MAGGIORE POLICLINICO   (Italy)

Author keywords

Cancer; Cis regulatory elements; DNA damage; Enhancer; Epigenetic; Metastasis; Reprogramming; Signaling pathways; Transcription factors; Tumor progression

Indexed keywords

HISTONE;

CANCER GROWTH; CANCER MORTALITY; CARCINOGENESIS; CELL PLASTICITY; CHROMATIN ASSEMBLY AND DISASSEMBLY; DNA METHYLATION; ENHANCER REGION; GENE MUTATION; HISTONE ACETYLATION; HISTONE METHYLATION; HUMAN; METASTASIS; NONHUMAN; NUCLEAR REPROGRAMMING; PROTEIN MODIFICATION; REGULATORY SEQUENCE; REVIEW; SIGNAL TRANSDUCTION; STRESS; ANIMAL; CELL TRANSFORMATION; DISEASE EXACERBATION; GENE EXPRESSION REGULATION; GENETICS; NEOPLASM; PATHOLOGY;

ANIMALS; CELL PLASTICITY; CELL TRANSFORMATION, NEOPLASTIC; CELLULAR REPROGRAMMING; DISEASE PROGRESSION; ENHANCER ELEMENTS, GENETIC; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; NEOPLASMS; SIGNAL TRANSDUCTION;

EID: 85045907266     PISSN: 1420682X     EISSN: 14209071     Source Type: Journal    
DOI: 10.1007/s00018-018-2820-1     Document Type: Review

References (177)

1. Koren S, Bentires-Alj M (2015) Breast tumor heterogeneity: source of fitness. Hurdle for therapy. Mol Cell 60:537–546
2. McDonald OG et al (2017) Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat Genet 49:367–376
3. Fujimoto A et al (2012) Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet 44:760–764
4. Kandoth C et al (2013) Mutational landscape and significance across 12 major cancer types. Nature 502:333–339
5. Stephens PJ et al (2012) The landscape of cancer genes and mutational processes in breast cancer. Nature 486:400–404
6. Sur I, Taipale J (2016) The role of enhancers in cancer. Nat Rev Cancer 16:483–493
7. Northcott PA et al (2014) Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 511:428–434
8. Zhang X et al (2016) Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers. Nat Genet 48:176–182
9. Hnisz D et al (2016) Activation of proto-oncogenes by disruption of chromosome neighborhoods. Science 351:1454–1458
10. Vogelstein B et al (2013) Cancer genome landscapes. Science 339:1546–1558
11. Long HK, Prescott SL, Wysocka J (2016) Ever-changing landscapes: transcriptional enhancers in development and evolution. Cell 167:1170–1187
12. Spitz F (2016) Gene regulation at a distance: from remote enhancers to 3D regulatory ensembles. Semin Cell Dev Biol 57:57–67
13. Andersson R et al (2014) An atlas of active enhancers across human cell types and tissues. Nature 507:455–461
14. Consortium, E.P (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489:57–74
15. Fukaya T, Lim B, Levine M (2016) Enhancer control of transcriptional bursting. Cell 166:358–368
16. Calo E, Wysocka J (2013) Modification of enhancer chromatin: what, how, and why? Mol Cell 49:825–837
17. Hnisz D et al (2013) Super-enhancers in the control of cell identity and disease. Cell 155:934–947
18. Whyte WA et al (2013) Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153:307–319
19. Panne D (2008) The enhanceosome. Curr Opin Struct Biol 18:236–242
20. Spitz F, Furlong EE (2012) Transcription factors: from enhancer binding to developmental control. Nat Rev Genet 13:613–626
21. Zaret KS, Mango SE (2016) Pioneer transcription factors, chromatin dynamics, and cell fate control. Curr Opin Genet Dev 37:76–81
22. Risca VI, Greenleaf WJ (2015) Unraveling the 3D genome: genomics tools for multiscale exploration. Trends Gene TIG 31:357–372
23. Shlyueva D, Stampfel G, Stark A (2014) Transcriptional enhancers: from properties to genome-wide predictions. Nat Rev Genet 15:272–286
24. Chen P, Wang Y, Li G (2014) Dynamics of histone variant H3.3 and its coregulation with H2A.Z at enhancers and promoters. Nucleus 5:21–27
25. Jin C, Felsenfeld G (2007) Nucleosome stability mediated by histone variants H3.3 and H2A.Z. Genes Dev 21:1519–1529
26. Jin C et al (2009) H3.3/H2A.Z double variant-containing nucleosomes mark ‘nucleosome-free regions’ of active promoters and other regulatory regions. Nat Genet 41:941–945
27. Barski A et al (2007) High-resolution profiling of histone methylations in the human genome. Cell 129:823–837
28. Pekowska A et al (2011) H3K4 tri-methylation provides an epigenetic signature of active enhancers. EMBO J 30:4198–4210
29. Garcia-Gonzalez E, Escamilla-Del-Arenal M, Arzate-Mejia R, Recillas-Targa F (2016) Chromatin remodeling effects on enhancer activity. Cell Mol Life Sci CMLS 73:2897–2910
30. Kim TK, Shiekhattar R (2015) Architectural and functional commonalities between enhancers and promoters. Cell 162:948–959
31. Chen X et al (2016) ATAC-see reveals the accessible genome by transposase-mediated imaging and sequencing. Nat Methods 13:1013–1020
32. Guo Y et al (2012) CTCF/cohesin-mediated DNA looping is required for protocadherin alpha promoter choice. Proc Natl Acad Sci USA 109:21081–21086
33. Kagey MH et al (2010) Mediator and cohesin connect gene expression and chromatin architecture. Nature 467:430–435
34. Xu Z, Wei G, Chepelev I, Zhao K, Felsenfeld G (2011) Mapping of INS promoter interactions reveals its role in long-range regulation of SYT8 transcription. Nat Struct Mol Biol 18:372–378
35. Yang J, Corces VG (2012) Insulators, long-range interactions, and genome function. Curr Opin Genet Dev 22:86–92
36. Reiter F, Wienerroither S, Stark A (2017) Combinatorial function of transcription factors and cofactors. Curr Opin Genet Dev 43:73–81
37. Kim TK et al (2010) Widespread transcription at neuronal activity-regulated enhancers. Nature 465:182–187
38. Li W, Notani D, Rosenfeld MG (2016) Enhancers as non-coding RNA transcription units: recent insights and future perspectives. Nat Rev Genet 17:207–223
39. Herz HM (2016) Enhancer deregulation in cancer and other diseases. BioEssays News Rev Mol Cell Dev Biol 38:1003–1015
40. Luo Z, Lin C (2016) Enhancer, epigenetics, and human disease. Curr Opin Genet Dev 36:27–33
41. Maurano MT et al (2012) Systematic localization of common disease-associated variation in regulatory DNA. Science 337:1190–1195
42. Schaub MA, Boyle AP, Kundaje A, Batzoglou S, Snyder M (2012) Linking disease associations with regulatory information in the human genome. Genome Res 22:1748–1759
43. Zhang X, Bailey SD, Lupien M (2014) Laying a solid foundation for Manhattan—’setting the functional basis for the post-GWAS era’. Trends Gene TIG 30:140–149
44. Khurana E et al (2016) Role of non-coding sequence variants in cancer. Nat Rev Genet 17:93–108
45. Oldridge DA et al (2015) Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism. Nature 528:418–421
46. Kandaswamy R et al (2016) Genetic predisposition to chronic lymphocytic leukemia is mediated by a BMF super-enhancer polymorphism. Cell Rep 16:2061–2067
47. Li Z et al (2017) APOBEC signature mutation generates an oncogenic enhancer that drives LMO1 expression in T-ALL. Leukemia 31:2057–2064
48. Hu S et al (2017) Whole-genome noncoding sequence analysis in T-cell acute lymphoblastic leukemia identifies oncogene enhancer mutations. Blood 129:3264–3268
49. Abraham BJ et al (2017) Small genomic insertions form enhancers that misregulate oncogenes. Nat Commun 8:14385
50. Mansour MR et al (2014) Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science 346:1373–1377
51. Navarro JM et al (2015) Site- and allele-specific polycomb dysregulation in T-cell leukaemia. Nat Commun 6:6094
52. Katainen R et al (2015) CTCF/cohesin-binding sites are frequently mutated in cancer. Nat Genet 47:818–821
53. Ji X et al (2016) 3D chromosome regulatory landscape of human pluripotent cells. Cell Stem Cell 18:262–275
54. Bailey SD et al (2015) ZNF143 provides sequence specificity to secure chromatin interactions at gene promoters. Nat Commun 2:6186
55. Bandopadhayay P et al (2016) MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat Genet 48:273–282
56. Drier Y et al (2016) An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma. Nat Genet 48:265–272
57. Weischenfeldt J et al (2017) Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking. Nat Genet 49:65–74
58. Groschel S et al (2014) A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. Cell 157:369–381
59. Zhang X et al (2017) Somatic super-enhancer duplications and hotspot mutations lead to oncogenic activation of the KLF5 transcription factor. Cancer Discov
60. Glodzik D et al (2017) A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers. Nat Genet 49:341–348
61. Faulkner GJ et al (2009) The regulated retrotransposon transcriptome of mammalian cells. Nat Genet 41:563–571
62. Gerdes P, Richardson SR, Mager DL, Faulkner GJ (2016) Transposable elements in the mammalian embryo: pioneers surviving through stealth and service. Genome Biol 17:100
63. Kunarso G et al (2010) Transposable elements have rewired the core regulatory network of human embryonic stem cells. Nat Genet 42:631–634
64. Burns KH (2017) Transposable elements in cancer. Nat Rev Cancer 17:415–424
65. de Souza FS, Franchini LF, Rubinstein M (2013) Exaptation of transposable elements into novel cis-regulatory elements: is the evidence always strong? Mol Biol Evol 30:1239–1251
66. Clayton EA et al (2016) Patterns of transposable element expression and insertion in cancer. Front Mol Biosci 3:76
67. Hu T et al (2017) Hypermethylated LTR retrotransposon exhibits enhancer activity. Epigenetics 12:226–237
68. Johnson KM, Taslim C, Saund RS, Lessnick SL (2017) Identification of two types of GGAA-microsatellites and their roles in EWS/FLI binding and gene regulation in Ewing sarcoma. PLoS ONE 12:e0186275
69. Fagnocchi L, Mazzoleni S, Zippo A (2016) Integration of signaling pathways with the epigenetic machinery in the maintenance of stem cells. Stem Cells Int 2016:8652748
70. Clevers H, Nusse R (2012) Wnt/beta-catenin signaling and disease. Cell 149:1192–1205
71. Hnisz D et al (2015) Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers. Mol Cell 58:362–370
72. Ryan RJH et al (2017) A B cell regulome links notch to downstream oncogenic pathways in small B cell lymphomas. Cell Rep 21:784–797
73. Nabet B et al (2015) Deregulation of the Ras-Erk signaling axis modulates the enhancer landscape. Cell Rep 12:1300–1313
74. Galli GG et al (2015) YAP drives growth by controlling transcriptional pause release from dynamic enhancers. Mol Cell 60:328–337
75. Franco HL, Nagari A, Kraus WL (2015) TNFalpha signaling exposes latent estrogen receptor binding sites to alter the breast cancer cell transcriptome. Mol Cell 58:21–34
76. Zanconato F et al (2015) Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat Cell Biol 17:1218–1227
77. Iwafuchi-Doi M, Zaret KS (2016) Cell fate control by pioneer transcription factors. Development 143:1833–1837
78. Bradner JE, Hnisz D, Young RA (2017) Transcriptional addiction in cancer. Cell 168:629–643
79. Bhagwat AS, Vakoc CR (2015) Targeting transcription factors in cancer. Trends Cancer 1:53–65
80. Pomerantz MM et al (2015) The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis. Nat Genet 47:1346–1351
81. Singhal H et al (2016) Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer. Sci Adv 2:e1501924
82. Shukla S et al (2017) Aberrant activation of a gastrointestinal transcriptional circuit in prostate cancer mediates castration resistance. Cancer Cell 32(6):792–806
83. Ge Y et al (2017) Stem cell lineage infidelity drives wound repair and cancer. Cell 169:636–650 (e614)
84. Boulay G et al (2017) OTX2 activity at distal regulatory elements shapes the chromatin landscape of group 3 medulloblastoma. Cancer Discov 7:288–301
85. Golson ML, Kaestner KH (2016) Fox transcription factors: from development to disease. Development 143:4558–4570
86. Fournier M et al (2016) FOXA and master transcription factors recruit Mediator and Cohesin to the core transcriptional regulatory circuitry of cancer cells. Sci Rep 6:34962
87. Jozwik KM, Chernukhin I, Serandour AA, Nagarajan S, Carroll JS (2016) FOXA1 directs H3K4 monomethylation at enhancers via recruitment of the methyltransferase MLL3. Cell Rep 17:2715–2723
88. Liu F et al (2015) EGFR mutation promotes glioblastoma through epigenome and transcription factor network remodeling. Mol Cell 60:307–318
89. Gryder BE et al (2017) PAX3-FOXO1 establishes myogenic super enhancers and confers BET bromodomain vulnerability. Cancer Discov 7:884–899
90. Ran L et al (2017) FOXF1 defines the core-regulatory circuitry in gastrointestinal stromal tumor (GIST). Cancer Discov 8(2):234–251
91. Kron KJ et al (2017) TMPRSS2-ERG fusion co-opts master transcription factors and activates NOTCH signaling in primary prostate cancer. Nat Genet 49:1336–1345
92. Thirant C et al (2017) ETO2-GLIS2 hijacks transcriptional complexes to drive cellular identity and self-renewal in pediatric acute megakaryoblastic leukemia. Cancer Cell 31:452–465
93. Zhao J et al (2016) Alterations of androgen receptor-regulated enhancer RNAs (eRNAs) contribute to enzalutamide resistance in castration-resistant prostate cancer. Oncotarget 7:38551–38565
94. Zhao Y et al (2016) Activation of P-TEFb by androgen receptor-regulated enhancer RNAs in castration-resistant prostate cancer. Cell Rep 15:599–610
95. Whyte WA et al (2012) Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. Nature 482:221–225
96. Fagnocchi L et al (2016) A Myc-driven self-reinforcing regulatory network maintains mouse embryonic stem cell identity. Nat Commun 7:11903
97. Fagnocchi L et al (2017) Multiple roles of MYC in integrating regulatory networks of pluripotent stem cells. Front Cell Dev Biol 5
98. Poli V et al (2018) MYC-driven epigenetic reprogramming favors the onset of tumorigenesis by inducing a stem cell-like state. Nat Commun 9:1024
99. Jagle S et al (2017) SNAIL1-mediated downregulation of FOXA proteins facilitates the inactivation of transcriptional enhancer elements at key epithelial genes in colorectal cancer cells. PLoS Genet 13:e1007109
100. Denny SK et al (2016) Nfib promotes metastasis through a widespread increase in chromatin accessibility. Cell 166:328–342
101. Roe JS et al (2017) Enhancer reprogramming promotes pancreatic cancer metastasis. Cell 170:875–888 (e820)
102. Verfaillie A et al (2015) Decoding the regulatory landscape of melanoma reveals TEADS as regulators of the invasive cell state. Nat Commun 6:6683
103. Yang H et al (2015) ETS family transcriptional regulators drive chromatin dynamics and malignancy in squamous cell carcinomas. eLife 4
104. Rhie SK et al (2016) Identification of activated enhancers and linked transcription factors in breast, prostate, and kidney tumors by tracing enhancer networks using epigenetic traits. Epigenet Chromatin 9:50
105. Yao L, Shen H, Laird PW, Farnham PJ, Berman BP (2015) Inferring regulatory element landscapes and transcription factor networks from cancer methylomes. Genome Biol 16:105
106. Morgan MA, Shilatifard A (2015) Chromatin signatures of cancer. Genes Dev 29:238–249
107. Sato T, Issa JJ, Kropf P (2017) DNA hypomethylating drugs in cancer therapy. Cold Spring Harb Perspect Med 7:1–14
108. Bell RE et al (2016) Enhancer methylation dynamics contribute to cancer plasticity and patient mortality. Genome Res 26:601–611
109. Fleischer T et al (2017) DNA methylation at enhancers identifies distinct breast cancer lineages. Nat Commun 8:1379
110. Heyn H et al (2016) Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer. Genome Biol 17:11
111. Vidal E et al (2017) A DNA methylation map of human cancer at single base-pair resolution. Oncogene 36:5648–5657
112. Cai Y et al (2017) Critical threshold levels of DNA methyltransferase 1 are required to maintain DNA methylation across the genome in human cancer cells. Genome Res 27:533–544
113. Lu R et al (2016) Epigenetic perturbations by Arg882-mutated DNMT3A potentiate aberrant stem cell gene-expression program and acute leukemia development. Cancer Cell 30:92–107
114. Yang L et al (2016) DNMT3A loss drives enhancer hypomethylation in FLT3-ITD-associated leukemias. Cancer Cell 29:922–934
115. Flavahan WA et al (2016) Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529:110–114
116. Sze CC, Shilatifard A (2014) MLL3/MLL4/COMPASS family on epigenetic regulation of enhancer function and cancer. Cold Spring Harb Perspect Med 6:1–15
117. Herz HM, Hu D, Shilatifard A (2014) Enhancer malfunction in cancer. Mol Cell 53:859–866
118. Prange KHM et al (2017) MLL-AF9 and MLL-AF4 oncofusion proteins bind a distinct enhancer repertoire and target the RUNX1 program in 11q23 acute myeloid leukemia. Oncogene 36:3346–3356
119. Clapier CR, Cairns BR (2009) The biology of chromatin remodeling complexes. Annu Rev Biochem 78:273–304
120. St Pierre R, Kadoch C (2017) Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities. Curr Opin Genet Dev 42:56–67
121. Mathur R et al (2017) ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Nat Genet 49:296–302
122. Kelso TWR et al (2017) Chromatin accessibility underlies synthetic lethality of SWI/SNF subunits in ARID1A-mutant cancers. eLife 6
123. Leong WZ et al (2017) ARID5B as a critical downstream target of the TAL1 complex that activates the oncogenic transcriptional program and promotes T-cell leukemogenesis. Genes Dev 31:2343–2360
124. Nakayama RT et al (2017) SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters. Nat Genet 49:1613–1623
125. Wang X et al (2017) SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation. Nat Genet 49:289–295
126. Zhang S et al (2017) INO80 is required for oncogenic transcription and tumor growth in non-small cell lung cancer. Oncogene 36:1430–1439
127. Zhou B et al (2016) INO80 governs superenhancer-mediated oncogenic transcription and tumor growth in melanoma. Genes Dev 30:1440–1453
128. Buschbeck M, Hake SB (2017) Variants of core histones and their roles in cell fate decisions, development and cancer. Nat Rev Mol Cell Biol 18:299–314
129. Zink LM, Hake SB (2016) Histone variants: nuclear function and disease. Curr Opin Genet Dev 37:82–89
130. Brunelle M et al (2015) The histone variant H2A.Z is an important regulator of enhancer activity. Nucleic Acids Res 43:9742–9756
131. Segala G, Bennesch MA, Pandey DP, Hulo N, Picard D (2016) Monoubiquitination of histone H2B blocks eviction of histone variant H2A.Z from inducible enhancers. Mol Cell 64:334–346
132. Valdes-Mora F et al (2017) Acetylated histone variant H2A.Z is involved in the activation of neo-enhancers in prostate cancer. Nat Commun 8:1346
133. Losada A (2014) Cohesin in cancer: chromosome segregation and beyond. Nat Rev Cancer 14:389–393
134. Marshall AD, Bailey CG, Rasko JE (2014) CTCF and BORIS in genome regulation and cancer. Curr Opin Genet Dev 24:8–15
135. Soutourina J (2017) Transcription regulation by the Mediator complex. Nat Rev Mol Cell Biol 19:262–274
136. Loven J et al (2013) Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153:320–334
137. Pelish HE et al (2015) Mediator kinase inhibition further activates super-enhancer-associated genes in AML. Nature 526:273–276
138. Murakami S, Nagari A, Kraus WL (2017) Dynamic assembly and activation of estrogen receptor alpha enhancers through coregulator switching. Genes Dev 31:1535–1548
139. Taberlay PC et al (2016) Three-dimensional disorganization of the cancer genome occurs coincident with long-range genetic and epigenetic alterations. Genome Res 26:719–731
140. Fiorito E et al (2016) CTCF modulates Estrogen Receptor function through specific chromatin and nuclear matrix interactions. Nucleic Acids Res 44:10588–10602
141. Cohen AJ et al (2017) Hotspots of aberrant enhancer activity punctuate the colorectal cancer epigenome. Nat Commun 8:14400
142. Rao SSP et al (2017) Cohesin loss eliminates all loop domains. Cell 171:305–320 (e324)
143. Ribich S, Harvey D, Copeland RA (2017) Drug discovery and chemical biology of cancer epigenetics. Cell Chem Biol 24:1120–1147
144. Shortt J, Ott CJ, Johnstone RW, Bradner JE (2017) A chemical probe toolbox for dissecting the cancer epigenome. Nat Rev Cancer 17:160–183
145. de Magalhaes JP (2013) How ageing processes influence cancer. Nat Rev Cancer 13:357–365
146. Zhang R, Chen HZ, Liu DP (2015) The four layers of aging. Cell Syst 1:180–186
147. Booth LN, Brunet A (2016) The aging epigenome. Mol Cell 62:728–744
148. Zaret KS, Carroll JS (2011) Pioneer transcription factors: establishing competence for gene expression. Genes Dev 25:2227–2241
149. Webb AE et al (2013) FOXO3 shares common targets with ASCL1 genome-wide and inhibits ASCL1-dependent neurogenesis. Cell Rep 4:477–491
150. Eijkelenboom A, Burgering BM (2013) FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol 14:83–97
151. Eijkelenboom A, Mokry M, Smits LM, Nieuwenhuis EE, Burgering BM (2013) FOXO3 selectively amplifies enhancer activity to establish target gene regulation. Cell Rep 5:1664–1678
152. Tubbs A, Nussenzweig A (2017) Endogenous DNA damage as a source of genomic instability in cancer. Cell 168:644–656
153. Dabin J, Fortuny A, Polo SE (2016) Epigenome maintenance in response to DNA damage. Mol Cell 62:712–727
154. Canela A et al (2017) Genome organization drives chromosome fragility. Cell 170:507–521 (e518)
155. Price BD, D’Andrea AD (2013) Chromatin remodeling at DNA double-strand breaks. Cell 152:1344–1354
156. Hauer MH et al (2017) Histone degradation in response to DNA damage enhances chromatin dynamics and recombination rates. Nat Struct Mol Biol 24:99–107
157. Lin C et al (2009) Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer. Cell 139:1069–1083
158. Perillo B et al (2008) DNA oxidation as triggered by H3K9me2 demethylation drives estrogen-induced gene expression. Science 319:202–206
159. Ju BG et al (2006) A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription. Science 312:1798–1802
160. Puc J et al (2015) Ligand-dependent enhancer activation regulated by topoisomerase-I activity. Cell 160:367–380
161. Periyasamy M et al (2015) APOBEC3B-mediated cytidine deamination is required for estrogen receptor action in breast cancer. Cell Rep 13:108–121
162. Le May N, Fradin D, Iltis I, Bougneres P, Egly JM (2012) XPG and XPF endonucleases trigger chromatin looping and DNA demethylation for accurate expression of activated genes. Mol Cell 47:622–632
163. Bansal K, Yoshida H, Benoist C, Mathis D (2017) The transcriptional regulator Aire binds to and activates super-enhancers. Nat Immunol 18:263–273
164. Massague J, Obenauf AC (2016) Metastatic colonization by circulating tumour cells. Nature 529:298–306
165. Makohon-Moore AP et al (2017) Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer. Nat Genet 49(3):358–366
166. Yates LR et al (2017) Genomic evolution of breast cancer metastasis and relapse. Cancer Cell 32:169–184 (e167)
167. Harper KL et al (2016) Mechanism of early dissemination and metastasis in Her2(+) mammary cancer. Nature
168. Hosseini H et al (2016) Early dissemination seeds metastasis in breast cancer. Nature
169. Lawson DA et al (2015) Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. Nature 526:131–135
170. Ozturk S et al (2016) SDPR functions as a metastasis suppressor in breast cancer by promoting apoptosis. Proc Natl Acad Sci USA 113:638–643
171. Pulecio J, Verma N, Mejia-Ramirez E, Huangfu D, Raya A (2017) CRISPR/Cas9-based engineering of the epigenome. Cell Stem Cell 21:431–447
172. Simeonov DR et al (2017) Discovery of stimulation-responsive immune enhancers with CRISPR activation. Nature 549:111–115
173. Mumbach MR et al (2017) Enhancer connectome in primary human cells identifies target genes of disease-associated DNA elements. Nat Genet 49:1602–1612
174. Fulco CP et al (2016) Systematic mapping of functional enhancer-promoter connections with CRISPR interference. Science 354:769–773
175. Kwiatkowski N et al (2014) Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 511:616–620
176. Rusan M et al (2018) Suppression of adaptive responses to targeted cancer therapy by transcriptional repression. Cancer Discov 8:59–73
177. Zawistowski JS et al (2017) Enhancer remodeling during adaptive bypass to MEK inhibition is attenuated by pharmacologic targeting of the P-TEFb complex. Cancer Discov 7:302–321