Artículo de Acceso Abierto. Puede ser descargado en su versión final
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor


Genomes contain the necessary information to ensure that genes are expressed in the right place, at the right time, and with the proper rate. Metazoan developmental genes often possess long stretches of DNA flanking their coding sequences and/or large introns which contain elements that influence gene expression. Most of these regulatory elements are relatively small and can be studied in isolation. For example, transcriptional enhancers, the elements that generate the expression pattern of a gene, have been traditionally studied with reporter constructs in transgenic animals. These studies have provided and will provide invaluable insights into enhancer evolution and function. However, this experimental approach has its limits; often, enhancer elements do not faithfully recapitulate native expression patterns. This fact suggests that additional information in cis-regulatory regions modulates the activity of enhancers and other regulatory elements. Indeed, recent studies have revealed novel functional aspects at the level of whole cis-regulatory regions. First, the discovery of "shadow enhancers." Second, the ubiquitous interactions between cis-regulatory elements. Third, the notion that some cis-regulatory regions may not function in a modular manner. Last, the effect of chromatin conformation on cis-regulatory activity. In this article, I describe these recent findings and discuss open questions in the field. © 2012 Wiley Periodicals, Inc.


Documento: Artículo
Título:Multiple layers of complexity in cis-regulatory regions of developmental genes
Autor:Frankel, N.
Filiación:Departamento de Ecología, Genética y Evolución, IEGEBA-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
Palabras clave:Chromatin conformation; Cis-regulatory elements; Cis-regulatory regions; Developmental genes; Regulatory-element interaction; Shadow enhancers; DNA; article; chromatin; cis regulatory region; conformational transition; developmental gene; DNA methylation; Drosophila melanogaster; embryo; embryo development; epigenetics; gene control; gene locus; nonhuman; priority journal; regulatory sequence; Animals; Animals, Genetically Modified; Chromatin Assembly and Disassembly; Enhancer Elements, Genetic; Gene Expression Regulation, Developmental; Humans; Animalia; Metazoa
Página de inicio:1857
Página de fin:1866
Título revista:Developmental Dynamics
Título revista abreviado:Dev. Dyn.
CAS:DNA, 9007-49-2


  • Adachi, Y., Hauck, B., Clements, J., Kawauchi, H., Kurusu, M., Totani, Y., Kang, Y.Y., Callaerts, P., Conserved cis-regulatory modules mediate complex neural expression patterns of the eyeless gene in the Drosophila brain (2003) Mech Dev, 120, pp. 1113-1126
  • Aday, A.W., Zhu, L.J., Lakshmanan, A., Wang, J., Lawson, N.D., Identification of cis regulatory features in the embryonic zebrafish genome through large-scale profiling of H3K4me1 and H3K4me3 binding sites (2011) Dev Biol, 357, pp. 450-462
  • Adkins, N.L., Hagerman, T.A., Georgel, P., GAGA protein: a multi-faceted transcription factor (2006) Biochem Cell Biol, 84, pp. 559-567
  • Agelopoulos, M., McKay, D.J., Mann, R.S., Developmental regulation of chromatin conformation by Hox proteins in Drosophila (2012) Cell Rep, 1, pp. 350-359
  • Akbari, O.S., Bousum, A., Bae, E., Drewell, R.A., Unraveling cis-regulatory mechanisms at the abdominal-A and abdominal-B genes in the Drosophila bithorax complex (2006) Dev Biol, 293, pp. 294-304
  • Akbari, O.S., Bae, E., Johnsen, H., Villaluz, A., Wong, D., Drewell, R.A., A novel promoter-tethering element regulates enhancer-driven gene expression at the bithorax complex in the Drosophila embryo (2008) Development, 135, pp. 123-131
  • Arnosti, D.N., Kulkarni, M.M., Transcriptional enhancers: intelligent enhanceosomes or flexible billboards? (2005) J Cell Biochem, 94, pp. 890-898
  • Banerji, J., Rusconi, S., Schaffner, W., Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences (1981) Cell, 27, pp. 299-308
  • Barlow, D.P., Genomic imprinting: a mammalian epigenetic discovery model (2011) Annu Rev Genet, 45, pp. 379-403
  • Barolo, S., Shadow enhancers: frequently asked questions about distributed cis-regulatory information and enhancer redundancy (2012) Bioessays, 34, pp. 135-141
  • Bell, A.C., West, A.G., Felsenfeld, G., Insulators and boundaries: versatile regulatory elements in the eukaryotic genome (2001) Science, 291, pp. 447-450
  • Blackledge, N.P., Klose, R., CpG island chromatin: a platform for gene regulation (2011) Epigenetics, 6, pp. 147-152
  • Bonn, S., Zinzen, R.P., Girardot, C., Gustafson, E.H., Perez-Gonzalez, A., Delhomme, N., Ghavi-Helm, Y., Furlong, E.E., Tissue-specific analysis of chromatin state identifies temporal signatures of enhancer activity during embryonic development (2012) Nat Genet, 44, pp. 148-156
  • Boyer, L.A., Plath, K., Zeitlinger, J., Brambrink, T., Medeiros, L.A., Lee, T.I., Levine, S.S., Jaenisch, R., Polycomb complexes repress developmental regulators in murine embryonic stem cells (2006) Nature, 441, pp. 349-353
  • Brinkman, A.B., Gu, H., Bartels, S.J., Zhang, Y., Matarese, F., Simmer, F., Marks, H., Stunnenberg, H.G., Sequential ChIP-bisulfite sequencing enables direct genome-scale investigation of chromatin and DNA methylation cross-talk (2012) Genome Res, 22, pp. 1128-1138
  • Calhoun, V.C., Stathopoulos, A., Levine, M., Promoter-proximal tethering elements regulate enhancer-promoter specificity in the Drosophila Antennapedia complex (2002) Proc Natl Acad Sci U S A, 99, pp. 9243-9247
  • Cande, J., Goltsev, Y., Levine, M.S., Conservation of enhancer location in divergent insects (2009) Proc Natl Acad Sci U S A, 106, pp. 14414-14419
  • Cedar, H., Bergman, Y., Programming of DNA methylation patterns (2012) Annu Rev Biochem, 81, pp. 97-117
  • Chao, C.H., Wang, H.D., Yuh, C.H., Complexity of cis-regulatory organization of six3a during forebrain and eye development in zebrafish (2010) BMC Dev Biol, 10, p. 35
  • Corbo, J.C., Lawrence, K.A., Karlstetter, M., Myers, C.A., Abdelaziz, M., Dirkes, W., Weigelt, K., Langmann, T., CRX ChIP-seq reveals the cis-regulatory architecture of mouse photoreceptors (2010) Genome Res, 20, pp. 1512-1525
  • Crocker, J., Tamori, Y., Erives, A., Evolution acts on enhancer organization to fine-tune gradient threshold readouts (2008) PLoS Biol, 6, pp. e263
  • Davis, G.K., Srinivasan, D.G., Wittkopp, P.J., Stern, D.L., The function and regulation of Ultrabithorax in the legs of Drosophila melanogaster (2007) Dev Biol, 308, pp. 621-631
  • Deaton, A.M., Bird, A., CpG islands and the regulation of transcription (2011) Genes Dev, 25, pp. 1010-1022
  • Dunipace, L., Ozdemir, A., Stathopoulos, A., Complex interactions between cis-regulatory modules in native conformation are critical for Drosophila snail expression (2011) Development, 138, pp. 4075-4084
  • Erives, A., Levine, M., Coordinate enhancers share common organizational features in the Drosophila genome (2004) Proc Natl Acad Sci U S A, 101, pp. 3851-3856
  • Estella, C., McKay, D.J., Mann, R.S., Molecular integration of wingless, decapentaplegic, and autoregulatory inputs into Distalless during Drosophila leg development (2008) Dev Cell, 14, pp. 86-96
  • Feng, S., Jacobsen, S.E., Reik, W., Epigenetic reprogramming in plant and animal development (2010) Science, 330, pp. 622-627
  • Franchini, L.F., Lopez-Leal, R., Nasif, S., Beati, P., Gelman, D.M., Low, M.J., de Souza, F.J., Rubinstein, M., Convergent evolution of two mammalian neuronal enhancers by sequential exaptation of unrelated retroposons (2011) Proc Natl Acad Sci U S A, 108, pp. 15270-15275
  • Frankel, N., Davis, G.K., Vargas, D., Wang, S., Payre, F., Stern, D.L., Phenotypic robustness conferred by apparently redundant transcriptional enhancers (2010) Nature, 466, pp. 490-493
  • Frankel, N., Erezyilmaz, D.F., McGregor, A.P., Wang, S., Payre, F., Stern, D.L., Morphological evolution caused by many subtle-effect substitutions in regulatory DNA (2011) Nature, 474, pp. 598-603
  • Frokjaer-Jensen, C., Davis, M.W., Ailion, M., Jorgensen, E.M., Improved Mos1-mediated transgenesis in C. elegans (2012) Nat Methods, 9, pp. 117-118
  • Fujioka, M., Yusibova, G.L., Patel, N.H., Brown, S.J., Jaynes, J.B., The repressor activity of Even-skipped is highly conserved, and is sufficient to activate engrailed and to regulate both the spacing and stability of parasegment boundaries (2002) Development, 129, pp. 4411-4421
  • Funahashi, J., Nakamura, H., Electroporation in avian embryos (2008) Methods Mol Biol, 461, pp. 377-382
  • Galindo, M.I., Fernandez-Garza, D., Phillips, R., Couso, J.P., Control of Distal-less expression in the Drosophila appendages by functional 3′ enhancers (2011) Dev Biol, 353, pp. 396-410
  • Ghiasvand, N.M., Rudolph, D.D., Mashayekhi, M., Brzezinski IV, J.A., Goldman, D., Glaser, T., Deletion of a remote enhancer near ATOH7 disrupts retinal neurogenesis, causing NCRNA disease (2011) Nat Neurosci, 14, pp. 578-586
  • Gibney, E.R., Nolan, C.M., Epigenetics and gene expression (2010) Heredity (Edinb), 105, pp. 4-13
  • Gonzalez, F., Duboule, D., Spitz, F., Transgenic analysis of Hoxd gene regulation during digit development (2007) Dev Biol, 306, pp. 847-859
  • Grau, D.J., Chapman, B.A., Garlick, J.D., Borowsky, M., Francis, N.J., Kingston, R.E., Compaction of chromatin by diverse Polycomb group proteins requires localized regions of high charge (2011) Genes Dev, 25, pp. 2210-2221
  • Guo, C., Yoon, H.S., Franklin, A., Jain, S., Ebert, A., Cheng, H.L., Hansen, E., Alt, F.W., CTCF-binding elements mediate control of V(D)J recombination (2011) Nature, 477, pp. 424-430
  • Hare, E.E., Peterson, B.K., Iyer, V.N., Meier, R., Eisen, M.B., Sepsid even-skipped enhancers are functionally conserved in Drosophila despite lack of sequence conservation (2008) PLoS Genet, 4, pp. e1000106
  • Heintzman, N.D., Hon, G.C., Hawkins, R.D., Kheradpour, P., Stark, A., Harp, L.F., Ye, Z., Ren, B., Histone modifications at human enhancers reflect global cell-type-specific gene expression (2009) Nature, 459, pp. 108-112
  • Hoch, M., Schroder, C., Seifert, E., Jackle, H., cis-acting control elements for Kruppel expression in the Drosophila embryo (1990) EMBO J, 9, pp. 2587-2595
  • Hong, J.W., Hendrix, D.A., Levine, M.S., Shadow enhancers as a source of evolutionary novelty (2008) Science, 321, p. 1314
  • Hornstein, E., Shomron, N., Canalization of development by microRNAs (2006) Nat Genet, 38 (SUPPL.), pp. S20-S24
  • Hunkapiller, J., Shen, Y., Diaz, A., Cagney, G., McCleary, D., Ramalho-Santos, M., Krogan, N., Reiter, J.F., Polycomb-like 3 promotes polycomb repressive complex 2 binding to CpG islands and embryonic stem cell self-renewal (2012) PLoS Genet, 8, pp. e1002576
  • Illingworth, R., Kerr, A., Desousa, D., Jorgensen, H., Ellis, P., Stalker, J., Jackson, D., Bird, A., A novel CpG island set identifies tissue-specific methylation at developmental gene loci (2008) PLoS Biol, 6, pp. e22
  • Isono, K., Fujimura, Y., Shinga, J., Yamaki, M., J, O.W., Takihara, Y., Murahashi, Y., Koseki, H., Mammalian polyhomeotic homologues Phc2 and Phc1 act in synergy to mediate polycomb repression of Hox genes (2005) Mol Cell Biol, 25, pp. 6694-6706
  • Istrail, S., Davidson, E.H., Logic functions of the genomic cis-regulatory code (2005) Proc Natl Acad Sci U S A, 102, pp. 4954-4959
  • Jeong, Y., El-Jaick, K., Roessler, E., Muenke, M., Epstein, D.J., A functional screen for sonic hedgehog regulatory elements across a 1 Mb interval identifies long-range ventral forebrain enhancers (2006) Development, 133, pp. 761-772
  • Jin, C., Zang, C., Wei, G., Cui, K., Peng, W., Zhao, K., Felsenfeld, G., H3.3/H2A.Z double variant-containing nucleosomes mark 'nucleosome-free regions' of active promoters and other regulatory regions (2009) Nat Genet, 41, pp. 941-945
  • Jing, H., Vakoc, C.R., Ying, L., Mandat, S., Wang, H., Zheng, X., Blobel, G.A., Exchange of GATA factors mediates transitions in looped chromatin organization at a developmentally regulated gene locus (2008) Mol Cell, 29, pp. 232-242
  • Kalay, G., Wittkopp, P.J., Nomadic enhancers: tissue-specific cis-regulatory elements of yellow have divergent genomic positions among Drosophila species (2010) PLoS Genet, 6, pp. e1001222
  • Kassis, J.A., Spatial and temporal control elements of the Drosophila engrailed gene (1990) Genes Dev, 4, pp. 433-443
  • Kazemian, M., Blatti, C., Richards, A., McCutchan, M., Wakabayashi-Ito, N., Hammonds, A.S., Celniker, S.E., Sinha, S., Quantitative analysis of the Drosophila segmentation regulatory network using pattern generating potentials (2010) PLoS Biol, p. 8
  • Kim, J., Lauderdale, J.D., Analysis of Pax6 expression using a BAC transgene reveals the presence of a paired-less isoform of Pax6 in the eye and olfactory bulb (2006) Dev Biol, 292, pp. 486-505
  • Klingler, M., Soong, J., Butler, B., Gergen, J.P., Disperse versus compact elements for the regulation of runt stripes in Drosophila (1996) Dev Biol, 177, pp. 73-84
  • L'Honore, A., Ouimette, J.F., Lavertu-Jolin, M., Drouin, J., Pitx2 defines alternate pathways acting through MyoD during limb and somitic myogenesis (2010) Development, 137, pp. 3847-3856
  • Laimins, L., Holmgren-Konig, M., Khoury, G., Transcriptional "silencer" element in rat repetitive sequences associated with the rat insulin 1 gene locus (1986) Proc Natl Acad Sci U S A, 83, pp. 3151-3155
  • Lanzuolo, C., Roure, V., Dekker, J., Bantignies, F., Orlando, V., Polycomb response elements mediate the formation of chromosome higher-order structures in the bithorax complex (2007) Nat Cell Biol, 9, pp. 1167-1174
  • Lee, A.P., Brenner, S., Venkatesh, B., Mouse transgenesis identifies conserved functional enhancers and cis-regulatory motif in the vertebrate LIM homeobox gene Lhx2 locus (2011) PLoS One, 6, pp. e20088
  • Lee, T.I., Jenner, R.G., Boyer, L.A., Guenther, M.G., Levine, S.S., Kumar, R.M., Chevalier, B., Young, R.A., Control of developmental regulators by Polycomb in human embryonic stem cells (2006) Cell, 125, pp. 301-313
  • Lettice, L.A., Heaney, S.J., Purdie, L.A., Li, L., de Beer, P., Oostra, B.A., Goode, D., de Graaff, E., A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly (2003) Hum Mol Genet, 12, pp. 1725-1735
  • Levine, M., Transcriptional enhancers in animal development and evolution (2010) Curr Biol, 20, pp. R754-R763
  • Li, X., Cassidy, J.J., Reinke, C.A., Fischboeck, S., Carthew, R.W., A microRNA imparts robustness against environmental fluctuation during development (2009) Cell, 137, pp. 273-282
  • Lieberman-Aiden, E., van Berkum, N.L., Williams, L., Imakaev, M., Ragoczy, T., Telling, A., Amit, I., Dekker, J., Comprehensive mapping of long-range interactions reveals folding principles of the human genome (2009) Science, 326, pp. 289-293
  • Lin, Q., Lin, L., Zhou, J., Chromatin insulator and the promoter targeting sequence modulate the timing of long-range enhancer-promoter interactions in the Drosophila embryo (2010) Dev Biol, 339, pp. 329-337
  • Ludwig, M.Z., Kreitman, M., Evolutionary dynamics of the enhancer region of even-skipped in Drosophila (1995) Mol Biol Evol, 12, pp. 1002-1011
  • Ludwig, M.Z., Manu, Kittler, R., White, K.P., Kreitman, M., Consequences of eukaryotic enhancer architecture for gene expression dynamics, development, and fitness (2011) PLoS Genet, 7, pp. e1002364
  • Maeda, R.K., Karch, F., The bithorax complex of Drosophila an exceptional Hox cluster (2009) Curr Top Dev Biol, 88, pp. 1-33
  • McBride, D.J., Buckle, A., van Heyningen, V., Kleinjan, D.A., DNaseI hypersensitivity and ultraconservation reveal novel, interdependent long-range enhancers at the complex Pax6 cis-regulatory region (2011) PLoS One, 6, pp. e28616
  • McGaughey, D.M., Vinton, R.M., Huynh, J., Al-Saif, A., Beer, M.A., McCallion, A.S., Metrics of sequence constraint overlook regulatory sequences in an exhaustive analysis at phox2b (2008) Genome Res, 18, pp. 252-260
  • Miele, A., Dekker, J., Mapping cis- and trans- chromatin interaction networks using chromosome conformation capture (3C) (2009) Methods Mol Biol, 464, pp. 105-121
  • Montavon, T., Soshnikova, N., Mascrez, B., Joye, E., Thevenet, L., Splinter, E., de Laat, W., Duboule, D., A regulatory archipelago controls Hox genes transcription in digits (2011) Cell, 147, pp. 1132-1145
  • Naranjo, S., Voesenek, K., de la Calle-Mustienes, E., Robert-Moreno, A., Kokotas, H., Grigoriadou, M., Economides, J., Gomez-Skarmeta, J.L., Multiple enhancers located in a 1-Mb region upstream of POU3F4 promote expression during inner ear development and may be required for hearing (2010) Hum Genet, 128, pp. 411-419
  • Negre, N., Brown, C.D., Ma, L., Bristow, C.A., Miller, S.W., Wagner, U., Kheradpour, P., White, K.P., A cis-regulatory map of the Drosophila genome (2011) Nature, 471, pp. 527-531
  • Nelson, C.E., Hersh, B.M., Carroll, S.B., The regulatory content of intergenic DNA shapes genome architecture (2004) Genome Biol, 5, pp. R25
  • Oda, M., Yamagiwa, A., Yamamoto, S., Nakayama, T., Tsumura, A., Sasaki, H., Nakao, K., Okano, M., DNA methylation regulates long-range gene silencing of an X-linked homeobox gene cluster in a lineage-specific manner (2006) Genes Dev, 20, pp. 3382-3394
  • Ogbourne, S., Antalis, T.M., Transcriptional control and the role of silencers in transcriptional regulation in eukaryotes (1998) Biochem J, 331 (PART 1), pp. 1-14
  • Ong, C.T., Corces, V.G., Enhancers: emerging roles in cell fate specification (2012) EMBO Rep, 13, pp. 423-430
  • Panne, D., Maniatis, T., Harrison, S.C., An atomic model of the interferon-beta enhanceosome (2007) Cell, 129, pp. 1111-1123
  • Pauls, S., Smith, S.F., Elgar, G., Lens development depends on a pair of highly conserved Sox21 regulatory elements (2012) Dev Biol, 365, pp. 310-318
  • Payre, F., Vincent, A., Carreno, S., ovo/svb integrates Wingless and DER pathways to control epidermis differentiation (1999) Nature, 400, pp. 271-275
  • Perry, M.W., Boettiger, A.N., Bothma, J.P., Levine, M., Shadow enhancers foster robustness of Drosophila gastrulation (2010) Curr Biol, 20, pp. 1562-1567
  • Perry, M.W., Boettiger, A.N., Levine, M., Multiple enhancers ensure precision of gap gene-expression patterns in the Drosophila embryo (2011) Proc Natl Acad Sci U S A, 108, pp. 13570-13575
  • Prazak, L., Fujioka, M., Gergen, J.P., Non-additive interactions involving two distinct elements mediate sloppy-paired regulation by pair-rule transcription factors (2010) Dev Biol, 344, pp. 1048-1059
  • Raisner, R.M., Hartley, P.D., Meneghini, M.D., Bao, M.Z., Liu, C.L., Schreiber, S.L., Rando, O.J., Madhani, H.D., Histone variant H2A.Z marks the 5′ ends of both active and inactive genes in euchromatin (2005) Cell, 123, pp. 233-248
  • Rangasamy, D., Berven, L., Ridgway, P., Tremethick, D.J., Pericentric heterochromatin becomes enriched with H2A.Z during early mammalian development (2003) EMBO J, 22, pp. 1599-1607
  • Schwartz, Y.B., Pirrotta, V., Polycomb complexes and epigenetic states (2008) Curr Opin Cell Biol, 20, pp. 266-273
  • Sing, A., Pannell, D., Karaiskakis, A., Sturgeon, K., Djabali, M., Ellis, J., Lipshitz, H.D., Cordes, S.P., A vertebrate Polycomb response element governs segmentation of the posterior hindbrain (2009) Cell, 138, pp. 885-897
  • Spencer, W.C., Zeller, G., Watson, J.D., Henz, S.R., Watkins, K.L., McWhirter, R.D., Petersen, S., Miller 3rd, D.M., A spatial and temporal map of C. elegans gene expression (2011) Genome Res, 21, pp. 325-341
  • Summerbell, D., Ashby, P.R., Coutelle, O., Cox, D., Yee, S., Rigby, P.W., The expression of Myf5 in the developing mouse embryo is controlled by discrete and dispersed enhancers specific for particular populations of skeletal muscle precursors (2000) Development, 127, pp. 3745-3757
  • Swami, M., Transcription: shadow enhancers confer robustness (2010) Nat Rev Genet, 11, p. 454
  • Swanson, C.I., Evans, N.C., Barolo, S., Structural rules and complex regulatory circuitry constrain expression of a Notch- and EGFR-regulated eye enhancer (2010) Dev Cell, 18, pp. 359-370
  • Tasic, B., Hippenmeyer, S., Wang, C., Gamboa, M., Zong, H., Chen-Tsai, Y., Luo, L., Site-specific integrase-mediated transgenesis in mice via pronuclear injection (2011) Proc Natl Acad Sci U S A, 108, pp. 7902-7907
  • Tolias, P.P., Kafatos, F.C., Functional dissection of an early Drosophila chorion gene promoter: expression throughout the follicular epithelium is under spatially composite regulation (1990) EMBO J, 9, pp. 1457-1464
  • Tsytsykova, A.V., Rajsbaum, R., Falvo, J.V., Ligeiro, F., Neely, S.R., Goldfeld, A.E., Activation-dependent intrachromosomal interactions formed by the TNF gene promoter and two distal enhancers (2007) Proc Natl Acad Sci U S A, 104, pp. 16850-16855
  • Udvardy, A., Maine, E., Schedl, P., The 87A7 chromomere. Identification of novel chromatin structures flanking the heat shock locus that may define the boundaries of higher order domains (1985) J Mol Biol, 185, pp. 341-358
  • Vakoc, C.R., Letting, D.L., Gheldof, N., Sawado, T., Bender, M.A., Groudine, M., Weiss, M.J., Blobel, G.A., Proximity among distant regulatory elements at the beta-globin locus requires GATA-1 and FOG-1 (2005) Mol Cell, 17, pp. 453-462
  • Venken, K.J., Bellen, H.J., Transgenesis upgrades for Drosophila melanogaster (2007) Development, 134, pp. 3571-3584
  • Venken, K.J., Carlson, J.W., Schulze, K.L., Pan, H., He, Y., Spokony, R., Wan, K.H., Hoskins, R.A., Versatile P[acman] BAC libraries for transgenesis studies in Drosophila melanogaster (2009) Nat Methods, 6, pp. 431-434
  • Vierra, D.A., Irvine, S.Q., Optimized conditions for transgenesis of the ascidian Ciona using square wave electroporation (2012) Dev Genes Evol, 222, pp. 55-61
  • Visser, M., Kayser, M., Palstra, R.J., HERC2 rs12913832 modulates human pigmentation by attenuating chromatin-loop formation between a long-range enhancer and the OCA2 promoter (2012) Genome Res, 22, pp. 446-455
  • Warming, S., Costantino, N., Court, D.L., Jenkins, N.A., Copeland, N.G., Simple and highly efficient BAC recombineering using galK selection (2005) Nucleic Acids Res, 33, pp. e36
  • Watts, J.A., Zhang, C., Klein-Szanto, A.J., Kormish, J.D., Fu, J., Zhang, M.Q., Zaret, K.S., Study of FoxA pioneer factor at silent genes reveals Rfx-repressed enhancer at Cdx2 and a potential indicator of esophageal adenocarcinoma development (2011) PLoS Genet, 7, pp. e1002277
  • Werner, T., Hammer, A., Wahlbuhl, M., Bosl, M.R., Wegner, M., Multiple conserved regulatory elements with overlapping functions determine Sox10 expression in mouse embryogenesis (2007) Nucleic Acids Res, 35, pp. 6526-6538
  • Whyte, W.A., Bilodeau, S., Orlando, D.A., Hoke, H.A., Frampton, G.M., Foster, C.T., Cowley, S.M., Young, R.A., Enhancer decommissioning by LSD1 during embryonic stem cell differentiation (2012) Nature, 482, pp. 221-225
  • Yoshida, C., Tokumasu, F., Hohmura, K.I., Bungert, J., Hayashi, N., Nagasawa, T., Engel, J.D., Igarashi, K., Long range interaction of cis-DNA elements mediated by architectural transcription factor Bach1 (1999) Genes Cells, 4, pp. 643-655
  • Yuh, C.H., Bolouri, H., Davidson, E.H., Cis-regulatory logic in the endo16 gene: switching from a specification to a differentiation mode of control (2001) Development, 128, pp. 617-629
  • Zeitlinger, J., Zinzen, R.P., Stark, A., Kellis, M., Zhang, H., Young, R.A., Levine, M., Whole-genome ChIP-chip analysis of Dorsal, Twist, and Snail suggests integration of diverse patterning processes in the Drosophila embryo (2007) Genes Dev, 21, pp. 385-390
  • Zhou, B., Pu, W.T., Isolation and characterization of embryonic and adult epicardium and epicardium-derived cells (2012) Methods Mol Biol, 843, pp. 155-168


---------- APA ----------
(2012) . Multiple layers of complexity in cis-regulatory regions of developmental genes. Developmental Dynamics, 241(12), 1857-1866.
---------- CHICAGO ----------
Frankel, N. "Multiple layers of complexity in cis-regulatory regions of developmental genes" . Developmental Dynamics 241, no. 12 (2012) : 1857-1866.
---------- MLA ----------
Frankel, N. "Multiple layers of complexity in cis-regulatory regions of developmental genes" . Developmental Dynamics, vol. 241, no. 12, 2012, pp. 1857-1866.
---------- VANCOUVER ----------
Frankel, N. Multiple layers of complexity in cis-regulatory regions of developmental genes. Dev. Dyn. 2012;241(12):1857-1866.