Transcriptional enhancers: From properties to genome-wide predictions

Nature Reviews Genetics

Volumn 15, Issue 4, 2014, Pages 272-286

  Shlyueva, Daria ^a   Stampfel, Gerald ^a   Stark, Alexander ^a  

^a RESEARCH INSTITUTE OF MOLECULAR PATHOLOGY   (Austria)

Author keywords

[No Author keywords available]

Indexed keywords

ANIMALS; BINDING SITES; CHROMATIN; ENHANCER ELEMENTS, GENETIC; EPIGENESIS, GENETIC; GENOME; GENOME-WIDE ASSOCIATION STUDY; HUMANS; TRANSCRIPTION FACTORS; TRANSCRIPTION, GENETIC;

EID: 84899450857     PISSN: 14710056     EISSN: 14710064     Source Type: Journal    
DOI: 10.1038/nrg3682     Document Type: Review

References (165)

1. Banerji, J., Rusconi, S. & Schaffner, W. Expression of a β-globin gene is enhanced by remote SV40 DNA sequences. Cell 27, 299-308 (1981
2. Banerji, J., Olson, L & Schaffner, W. A lymphocyte-specific cellular enhancer is located downstream of the joining region in immunoglobulin heavy chain genes. 33, 729-740 (1983
3. Amano, T. et al. Chromosomal dynamics at the shh locus: Limb bud-specific differential regulation of competence and active transcription. Dev. Cell 16, 47-57 (2009
4. Arnone, M. I. & Davidson, E. H. The hardwiring of development: Organization and function of genomic regulatory systems. Development 124, 1851-1864 (1997
5. Dawson, M. A. & Kouzarides, T. Cancer epigenetics: From mechanism to therapy. Cell 150, 12-27 (2012
6. Carroll, S. B. Evo-devo and an expanding evolutionary synthesis: A genetic theory of morphological evolution. Cell 134, 25-36 (2008
7. Visel, A., Rubin, E. M. & Pennacchio, L. A. Genomic views of distant-Acting enhancers. Nature 461, 199-205 (2009
8. Yáñez-Cuna, J. O., Kvon, E. Z. & Stark, A. Deciphering the transcriptional cis-regulatory code. Trends Genet. 29, 11-22 (2013
9. Tomancak, P. et al. Systematic determination of patterns of gene expression during Drosophila embryogenesis. Genome Biol. 3, research0088 0088.14 (2002
10. Richardson, L. et al. EMAGE mouse embryo spatial gene expression database: 2010 update. Nucleic Acids Res. 38, D703-D709 (2010
11. International HapMap 3 Consortium. Integrating common and rare genetic variation in diverse human populations. Nature 467, 52-58 (2010
12. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57-74 (2012
13. The modENCODE Consortium. Identification of functional elements and regulatory circuits by Drosophila modENCODE. Science 330, 1787-1797 (2010
14. Tjian, R. The binding site on SV40 DNA for a T antigen-related protein. Cell 13, 165-179 (1978
15. Giniger, E., Varnum, S. M. & Ptashne, M. Specific DNA binding of GAL4, a positive regulatory protein of yeast. Cell 40, 767-774 (1985
16. Berman, B. P. et al. Exploiting transcription factor binding site clustering to identify cis-regulatory modules involved in pattern formation in the Drosophila genome. Proc. Natl. Acad. Sci. USA 99, 757-762 (2002
17. Kheradpour, P., Stark, A., Roy, S. & Kellis, M. Reliable prediction of regulator targets using 12 Drosophila genomes. Genome Res. 17, 1919-1931 (2007
18. Del Bene, F. et al. In vivo validation of a computationally predicted conserved Ath5 target gene set. PLoS Genet. 3, 1661-1671 (2007
19. Hallikas, O. et al. Genome-wide prediction of mammalian enhancers based on analysis of transcription-factor binding affinity. Cell 124, 47-59 (2006
20. Sinha, S., van Nimwegen, E. & Siggia, E. D. A probabilistic method to detect regulatory modules. Bioinformatics 19, i292-i301 (2003
21. Herrmann, C., Van de Sande, B., Potier, D. & Aerts, S. i cisTarget: An integrative genomics method for the prediction of regulatory features and cis-regulatory modules. Nucleic Acids Res. 40, e114 (2012
22. Warner, J. B. et al. Systematic identification of mammalian regulatory motifs' target genes and functions. Nature Methods 5, 347-353 (2008
23. Aerts, S. Computational strategies for the genome-wide identification of cis-regulatory elements and transcriptional targets. Curr. Top. Dev. Biol. 98, 121-145 (2012
24. Hardison, R. C. & Taylor, J. Genomic approaches towards finding cis-regulatory modules in animals. Nature Rev. Genet.13, 469-483 (2012
25. Wei, G. H. et al. Genome-wide analysis of ETS-family DNA-binding in vitro and in vivo. EMBO J. 29, 2147-2160 (2010
26. Jolma, A. et al. DNA-binding specificities of human transcription factors. Cell 152, 327-339 (2013
27. Noyes, M. B. et al. Analysis of homeodomain specificities allows the family-wide prediction of preferred recognition sites. Cell 133, 1277-1289 (2008
28. Yanez-Cuna, J. O., Dinh, H. Q., Kvon, E. Z., Shlyueva, D. & Stark, A. Uncovering cis-regulatory sequence requirements for context-specific transcription factor binding. Genome Res. 22, 2018-2030 (2012
29. Slattery, M. et al. Cofactor binding evokes latent differences in DNA binding specificity between Hox proteins. Cell 147, 1270-1282 (2011
30. Blow, M. J. et al. ChIP-seq identification of weakly conserved heart enhancers. Nature Genet. 42, 818-822 (2010
31. Meireles-Filho, A. C. A. & Stark, A. Comparative genomics of gene regulation-conservation and divergence of cis-regulatory information. Curr. Opin. Genet. Dev. 19, 565-570 (2009
32. Kantorovitz, M. R. et al. Motif-blind, genome-wide discovery of cis-regulatory modules in Drosophila and mouse. Dev. Cell 17, 568-579 (2009
33. Narlikar, L. et al. Genome-wide discovery of human heart enhancers. Genome Res. 20, 381-392 (2010
34. Burzynski, G. M. et al. Systematic elucidation and in vivo validation of sequences enriched in hindbrain transcriptional control. Genome Res. 22, 2278-2289 (2012
35. Johnson, D. S., Mortazavi, A., Myers, R. M. & Wold, B. Genome-wide mapping of in vivo protein-DNA interactions. Science 316, 1497-1502 (2007
36. Robertson, G. et al. Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing. Nature Methods 4, 651-657 (2007
37. Rhee, H. S. & Pugh, B. F. Comprehensive genome-wide protein-DNA interactions detected at single-nucleotide resolution. Cell 147, 1408-1419 (2011
38. van Steensel, B. & Henikoff, S. Identification of in vivo DNA targets of chromatin proteins using tethered Dam methyltransferase. Nature Biotech. 18, 424-428 (2000
39. Spitz, F. & Furlong, E. E. Transcription factors: From enhancer binding to developmental control. Nature Rev. Genet. 13, 613-626 (2012
40. Sandmann, T. et al. A core transcriptional network for early mesoderm development in Drosophila melanogaster. Genes Dev. 21, 436-449 (2007
41. Zeitlinger, J. et al. Whole-genome ChIP-chip analysis of Dorsal, Twist, and Snail suggests integration of diverse patterning processes in the Drosophila embryo. Genes Dev. 21, 385-390 (2007
42. Li, X. Y. et al. Transcription factors bind thousands of active and inactive regions in the Drosophila blastoderm. PLoS Biol. 6, e27 (2008
43. Kvon, E. Z., Stampfel, G., Yáñez-Cuna, J. O., Dickson, B. J. & Stark, A. HOT regions function as patterned developmental enhancers and have a distinct cis-regulatory signature. Genes Dev. 26, 908-913 (2012
44. Fisher, W. W. et al. DNA regions bound at low occupancy by transcription factors do not drive patterned reporter gene expression in Drosophila. Proc. Natl Acad. Sci. 109, 21330-21335 (2012
45. Hammar, P. et al. The lac repressor displays facilitated diffusion in living cells. Science 336, 1595-1598 (2012
46. Teytelman, L., Thurtle, D. M., Rine, J. & van Oudenaarden, A. Highly expressed loci are vulnerable to misleading ChIP localization of multiple unrelated proteins. Proc. Natl Acad. Sci. 110, 18602-18607 (2013
47. Poorey, K. et al. Measuring chromatin interaction dynamics on the second time scale at single-copy genes. Science 342, 369-372 (2013
48. Lickwar, C. R., Mueller, F., Hanlon, S. E., McNally, J. G. & Lieb, J. D. Genome-wide protein-DNA binding dynamics suggest a molecular clutch for transcription factor function. Nature 484, 251-255 (2013
49. Moorman, C. et al. Hotspots of transcription factor colocalization in the genome of Drosophila melanogaster. Proc. Natl Acad. Sci. USA 103, 12027-12032 (2006
50. Visel, A. et al. ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457, 854-858 (2009
51. Heintzman, N. D. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nature Genet. 39, 311-318 (2007
52. Rada-Iglesias, A. et al. A unique chromatin signature uncovers early developmental enhancers in humans. Nature 470, 279-283 (2011
53. Visel, A. et al. A high-resolution enhancer atlas of the developing telencephalon. Cell 152, 895-908 (2013
54. May, D. et al. Large-scale discovery of enhancers from human heart tissue. Nature Genet. 44, 89-93 (2012
55. Filion, G. J. et al. Systematic protein location mapping reveals five principal chromatin types in Drosophila cells. Cell 143, 212-224 (2010
56. van Bemmel, J. G. et al. A network model of the molecular organization of chromatin in Drosophila. Mol. Cell 49, 759-771 (2013
57. Ram, O. et al. Combinatorial patterning of chromatin regulators uncovered by genome-wide location analysis in human cells. Cell 147, 1628-1639 (2011
58. Weintraub, H. & Groudine, M. Chromosomal subunits in active genes have an altered conformation. Science 193, 848-856 (1976
59. Axel, R., Cedar, H. & Felsenfeld, G. Synthesis of globin ribonucleic acid from duck-reticulocyte chromatin in vitro. Proc. Natl. Acad. Sci. USA 70, 2029-2032 (1973
60. Boyle, A. P. et al. High-resolution mapping and characterization of open chromatin across the genome. Cell 132, 311-322 (2008
61. Yuan, G. C. et al. Genome-scale identification of nucleosome positions in S. cerevisiae. Science 309, 626-630 (2005
62. Neph, S. et al. An expansive human regulatory lexicon encoded in transcription factor footprints. Nature 488, 83-90 (2012
63. Giresi, P. G., Kim, J., McDaniell, R. M., Iyer, V. R. & Lieb, J. D. FAIRE (formaldehyde-Assisted isolation of regulatory elements) isolates active regulatory elements from human chromatin. Genome Res. 17, 877-885 (2007
64. Bell, O., Tiwari, V. K., Thomä, N. H. & Schübeler, D. Determinants and dynamics of genome accessibility. Nature Rev. Genet.12, 554-564 (2011
65. Zaret, K. S. & Carroll, J. S. Pioneer transcription factors: Establishing competence for gene expression. Genes Dev. 25, 2227-2241 (2011
66. Mirny, L. A. Nucleosome-mediated cooperativity between transcription factors. Proc. Natl Acad. Sci. 107, 22534-22539 (2010
67. Miller, J. A. & Widom, J. Collaborative competition mechanism for gene activation in vivo. Mol. Cell. Biol. 23, 1623-1632 (2003
68. Pique-Regi, R. et al. Accurate inference of transcription factor binding from DNA sequence and chromatin accessibility data. Genome Res. 21, 447-455 (2011
69. Kaplan, T. et al. Quantitative models of the mechanisms that control genome-wide patterns of transcription factor binding during early Drosophila development. PLoS Genet. 7, e1001290 (2011
70. Heintzman, N. D. et al. Histone modifications at human enhancers reflect global cell-Type-specific gene expression. Nature 459, 108-112 (2009
71. Thurman, R. E. et al. The accessible chromatin landscape of the human genome. Nature 488, 75-82 (2013
72. Arnold, C. D. et al. Genome-wide quantitative enhancer activity maps identified by STARR-seq. Science 339, 1074-1077 (2013
73. Xi, H. et al. Identification and characterization of cell type-specific and ubiquitous chromatin regulatory structures in the human genome. PLoS Genet. 3, e136 (2007
74. Gray, S. & Levine, M. Transcriptional repression in development. Curr. Opin. Cell Biol. 8, 358-364 (1996
75. Cochella, L. & Hobert, O. Embryonic priming of a miRNA locus predetermines postmitotic neuronal left/right asymmetry in C. elegans. Cell 151, 1229-1242 (2012
76. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693-705 (2007
77. Roh, T. Y., Cuddapah, S. & Zhao, K. Active chromatin domains are defined by acetylation islands revealed by genome-wide mapping. Genes Dev. 19, 542-552 (2005
78. Bonn, S. et al. Tissue-specific analysis of chromatin state identifies temporal signatures of enhancer activity during embryonic development. Nature Genet. 44, 148-156 (2012
79. Peters, A. H. F. M. et al. Histone H3 lysine 9 methylation is an epigenetic imprint of facultative heterochromatin. Nature Genet. 30, 77-80 (2002
80. Simon, J. A. & Kingston, R. E. Mechanisms of Polycomb gene silencing: Knowns and unknowns. Nature Rev. Mol. Cell. Biol. 10, 697-708 (2009
81. Wamstad, J. A. et al. Dynamic and coordinated epigenetic regulation of developmental transitions in the cardiac lineage. Cell 151, 206-220 (2012
82. Shen, Y. et al. A map of the cis-regulatory sequences in the mouse genome. Nature 488, 116-120 (2012
83. Kharchenko, P. V. et al. Comprehensive analysis of the chromatin landscape in Drosophila melanogaster. Nature 471, 480-485 (2012
84. Ernst, J. et al. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473, 43-49 (2011
85. Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315-326 (2006
86. Ostuni, R. et al. Latent enhancers activated by stimulation in differentiated cells. Cell 152, 157-171 (2013
87. Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823-837 (2007
88. Hah, N. et al. A rapid, extensive, and transient transcriptional response to estrogen signaling in breast cancer cells. Cell 145, 622-634 (2011
89. Core, L. J. et al. Defining the status of RNA polymerase at promoters. Cell Rep. 2, 1025-1035 (2012
90. Kim, T. K. et al. Widespread transcription at neuronal activity-regulated enhancers. Nature 465, 182-187 (2010
91. De Santa, F. et al. A large fraction of extragenic RNA pol II transcription sites overlap enhancers. PLoS Biol. 8, e1000384 (2010
92. Lai, F. et al. Activating RNAs associate with Mediator to enhance chromatin architecture and transcription. Nature 494, 497-501 (2013
93. Natoli, G. & Andrau, J. C. Noncoding transcription at enhancers: General principles and functional models. Annu. Rev. Genet. 46, 1-19 (2012
94. Ebisuya, M., Yamamoto, T., Nakajima, M. & Nishida, E. Ripples from neighbouring transcription. Nature Cell Biol. 10, 1106-1113 (2008
95. Ponting, C. P., Oliver, P. L. & Reik, W. Evolution and functions of long noncoding RNAs. Cell 136, 629-641 (2009
96. Ernst, J. & Kellis, M. ChromHMM: Automating chromatin-state discovery and characterization. Nature Methods 9, 215-216 (2012
97. Hödl, M. & Basler, K. Transcription in the absence of histone H3.2 and H3K4 methylation. Curr. Biol. 22, 2253-2257 (2012
98. Pengelly, A. R., Copur, O., Jackle, H., Herzig, A. & Muller, J. A. Histone mutant reproduces the phenotype caused by loss of histone-modifying factor Polycomb. Science 339, 698-699 (2013
99. Hathaway, N. A. et al. Dynamics and memory of heterochromatin in living cells. Cell 149, 1447-1460 (2012
100. Calo, E. & Wysocka, J. Modification of enhancer chromatin: What, how, and why? Mol. Cell 49, 825-837 (2013
101. Kagey, M. H. et al. Mediator and cohesin connect gene expression and chromatin architecture. Nature 467, 430-435 (2010
102. Schmidt, D. et al. A CTCF-independent role for cohesin in tissue-specific transcription. Genome Res. 20, 578-588 (2010
103. Whyte, W. A. et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307-319 (2013
104. van Steensel, B. & Dekker, J. Genomics tools for unraveling chromosome architecture. Nature Biotech. 28, 1089-1095 (2010
105. Fullwood, M. J. et al. An oestrogen-receptor-α-bound human chromatin interactome. Nature 461, 58-64 (2009
106. Li, G. et al. Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell 148, 84-98 (2012
107. Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289-293 (2009
108. Sexton, T. et al. Three-dimensional folding and functional organization principles of the Drosophila genome. Cell 148, 458-472 (2012
109. Jin, F. et al. A high-resolution map of the three-dimensional chromatin interactome in human cells. Nature 503, 290-294 (2013
110. Gibcus, J. H. & Dekker, J. The hierarchy of the 3D genome. Mol. Cell 49, 773-782 (2013
111. de Laat, W. & Duboule, D. Topology of mammalian developmental enhancers and their regulatory landscapes. Nature 502, 499-506 (2013
112. Sanyal, A., Lajoie, B. R., Jain, G. & Dekker, J. The long-range interaction landscape of gene promoters. Nature 489, 109-113 (2013
113. Lettice, L. A. A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum. Mol. Genet. 12, 1725-1735 (2003
114. Sur, I. K. et al. Mice lacking a Myc enhancer that includes human SNP rs6983267 are resistant to intestinal tumors. Science 338, 1360-1363 (2012
115. Huang, F. W. et al. Highly recurrent TERT promoter mutations in human melanoma. Science 339, 957-959 (2013
116. Zeitlinger, J. & Stark, A. Developmental gene regulation in the era of genomics. Dev. Biol. 339, 230-239 (2010
117. Crocker, J. & Stern, D. L. TALE-mediated modulation of transcriptional enhancers in vivo. Nature Methods 10, 762-767 (2013
118. Zhang, Y. et al. Chromatin connectivity maps reveal dynamic promoter-enhancer long-range associations. Nature 504, 306-310 (2013
119. Kieffer-Kwon, K. R. et al. Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation. Cell 155, 1507-1520 (2013
120. Zinzen, R. P., Girardot, C., Gagneur, J., Braun, M. & Furlong, E. E. M. Combinatorial binding predicts spatio-Temporal cis-regulatory activity. Nature 462, 65-70 (2009
121. Manning, L. et al. A resource for manipulating gene expression and analyzing cis-regulatory modules in the Drosophila CNS. Cell Rep. 2, 1002-1013 (2012
122. Dupuy, D. A. First version of the Caenorhabditis elegans promoterome. Genome Res. 14, 2169-2175 (2004
123. Visel, A., Minovitsky, S., Dubchak, I. & Pennacchio, L. A. VISTA enhancer browser-A database of tissue-specific human enhancers. Nucleic Acids Res. 35, D88-D92 (2007
124. Gisselbrecht, S. S. et al. Highly parallel assays of tissue-specific enhancers in whole Drosophila embryos. Nature Methods 10, 774-780 (2013
125. Nam, J. & Davidson, E. H. Barcoded DNA-Tag reporters for multiplex cis-regulatory analysis. PLoS ONE 7, e35934 (2012
126. Melnikov, A. et al. Systematic dissection and optimization of inducible enhancers in human cells using a massively parallel reporter assay. Nature Biotech. 30, 271-277 (2012
127. Patwardhan, R. P. et al. Massively parallel functional dissection of mammalian enhancers in vivo. Nature Biotech. 30, 265-270 (2012
128. Kwasnieski, J. C., Mogno, I., Myers, C. A., Corbo, J. C. & Cohen, B. A. Complex effects of nucleotide variants in a mammalian cis-regulatory element. Proc. Natl. Acad. Sci. 109, 19498-19503 (2012
129. Sharon, E. et al. Inferring gene regulatory logic from high-Throughput measurements of thousands of systematically designed promoters. Nature Biotech. 30, 521-530 (2012
130. Smith, R. P. et al. Massively parallel decoding of mammalian regulatory sequences supports a flexible organizational model. Nature Genet. 45, 1021-1028 (2013
131. Gertz, J., Siggia, E. D. & Cohen, B. A. Analysis of combinatorial cis-regulation in synthetic and genomic promoters. Nature 457, 215-218 (2008
132. Steiner, F. A., Talbert, P. B., Kasinathan, S., Deal, R. B. & Henikoff, S. Cell-Type-specific nuclei purification from whole animals for genome-wide expression and chromatin profiling. Genome Res. 22, 766-777 (2012
133. Adli, M. & Bernstein, B. E. Whole-genome chromatin profiling from limited numbers of cells using nano-ChIP-seq. Nature Protoc. 6, 1656-1668 (2011
134. Nagano, T. et al. Single-cell Hi C reveals cell to cell variability in chromosome structure. Nature 502, 59-64 (2013
135. Buenrostro, J. D., Giresi, P. G., Zaba, L. C., Chang, H. Y. & Greenleaf, W. J. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nature Methods 10, 1213-1218 (2013
136. Deng, Q., Ramsköld, D., Reinius, B. & Sandberg, R. Single-cell RNA-seq reveals dynamic, random monoallelic gene expression in mammalian cells. Science 343, 193-196 (2014
137. Gilbert, L. A. et al. CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell 154, 442-451 (2013
138. Mendenhall, E. M. et al. Locus-specific editing of histone modifications at endogenous enhancers. Nature Biotech. 31, 1133-1136 (2013
139. Konermann, S. et al. Optical control of mammalian endogenous transcription and epigenetic states. Nature 500, 472-476 (2013
140. Reyon, D. et al. FLASH assembly of TALENs for high-Throughput genome editing. Nature Biotech. 30, 460-465 (2012
141. Jinek, M. et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337, 816-821 (2012
142. Mali, P et al. RNA-guided human genome engineering via Cas9. Science 339, 823-826 (2013
143. Ruf, S. et al. Large-scale analysis of the regulatory architecture of the mouse genome with a transposon-Associated sensor. Nature Genet. 43, 379-386 (2011
144. Mollereau, B. et al. A green fluorescent protein enhancer trap screen in Drosophila photoreceptor cells. Mech. Dev. 93, 151-160 (2000
145. Akhtar, W. et al. Chromatin position effects assayed by thousands of reporters integrated in parallel. Cell 154, 914-927 (2013
146. Maurano, M. T. et al. Systematic localization of common disease-Associated variation in regulatory DNA. Science 337, 1190-1195 (2012
147. Lovén, J. et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320-334 (2013
148. Shi, J. et al. Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation. Genes Dev. 27, 2648-2662 (2013
149. Zuber, J. et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478, 524-528 (2011
150. Delmore, J. E. et al. BET bromodomain inhibition as a therapeutic strategy to target c Myc. Cell 146, 904-917 (2011
151. Knutson, S. K. et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nature Chem. Biol. 8, 890-896 (2012
152. Herrmann, H. et al. Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem-And progenitor cells in acute myeloid leukemia AML. Oncotarget 3, 1588-1599 (2012
153. Stormo, G. D. & Zhao, Y. Determining the specificity of protein-DNA interactions. Nature Rev. Genet. 11, 751-760 (2010
154. Roth, F. P., Hughes, J. D., Estep, P. W. & Church, G. M. Finding DNA regulatory motifs within unaligned noncoding sequences clustered by whole-genome mRNA quantitation. Nature Biotech. 16, 939-945 (1998
155. Kellis, M., Patterson, N., Endrizzi, M., Birren, B. & Lander, E. S. Sequencing and comparison of yeast species to identify genes and regulatory elements. Nature 423, 241-254 (2003
156. Bosch, J. R., Benavides, J. A. & Cline, T. W. The TAGteam DNA motif controls the timing of Drosophila pre-blastoderm transcription. Development 133, 1967-1977 (2006
157. Liang, H. L. et al. The zinc-finger protein Zelda is a key activator of the early zygotic genome in Drosophila. Nature 456, 400-403 (2008
158. Bulyk, M. L., Gentalen, E., Lockhart, D. J. & Church, G. M. Quantifying DNA-protein interactions by double-stranded DNA arrays. Nature Biotech. 17, 573-577 (1999
159. Tuerk, C. & Gold, L. Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 249, 505-510 (1990
160. Li, J. J. & Herskowitz, I. Isolation of ORC6, a component of the yeast origin recognition complex by a one-hybrid system. Science 262, 1870-1874 (1993
161. Meng, X., Brodsky, M. H. & Wolfe, S. A. A bacterial one-hybrid system for determining the DNA-binding specificity of transcription factors. Nature Biotech. 23, 988-994 (2005
162. Matys, V. et al. TRANSFAC and its module TRANSCompel: Transcriptional gene regulation in eukaryotes. Nucleic Acids Res. 34, D108-D110 (2006
163. Portales-Casamar, E. et al. JASPAR 2010: The greatly expanded open-Access database of transcription factor binding profiles. Nucleic Acids Res. 38, D105-D110 (2010
164. Newburger, D. E. & Bulyk, M. L. UniPROBE: An online database of protein binding microarray data on protein-DNA interactions. Nucleic Acids Res. 37, D77-D82 (2009
165. Mogno, I., Kwasnieski, J. C. & Cohen, B. A. Massively parallel synthetic promoter assays reveal the in vivo effects of binding site variants. Genome Res. 23, 1908-1915 (2013