Transcription factors: from enhancer binding to developmental control (original) (raw)

• Davidson, E. H. Emerging properties of animal gene regulatory networks. Nature 468, 911–920 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Peter, I. S. & Davidson, E. H. Evolution of gene regulatory networks controlling body plan development. Cell 144, 970–985 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Lenhard, B., Sandelin, A. & Carninci, P. Metazoan promoters: emerging characteristics and insights into transcriptional regulation. Nature Rev. Genet. 13, 233–245 (2012).
  Article CAS PubMed Google Scholar
• Levine, M. Transcriptional enhancers in animal development and evolution. Curr. Biol. 20, R754–R763 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Bulger, M. & Groudine, M. Functional and mechanistic diversity of distal transcription enhancers. Cell 144, 327–339 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Petrykowska, H. M., Vockley, C. M. & Elnitski, L. Detection and characterization of silencers and enhancer-blockers in the greater CFTR locus. Genome Res. 18, 1238–1246 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Vokes, S. A., Ji, H., Wong, W. H. & McMahon, A. P. A genome-scale analysis of the _cis_-regulatory circuitry underlying sonic hedgehog-mediated patterning of the mammalian limb. Genes Dev. 22, 2651–2663 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Ayer, S. & Benyajati, C. Conserved enhancer and silencer elements responsible for differential Adh transcription in Drosophila cell lines. Mol. Cell. Biol. 10, 3512–3523 (1990).
  Article CAS PubMed PubMed Central Google Scholar
• Gaszner, M. & Felsenfeld, G. Insulators: exploiting transcriptional and epigenetic mechanisms. Nature Rev. Genet. 7, 703–713 (2006).
  Article CAS PubMed Google Scholar
• Ohtsuki, S., Levine, M. & Cai, H. N. Different core promoters possess distinct regulatory activities in the Drosophila embryo. Genes Dev. 12, 547–556 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Calhoun, V. C., Stathopoulos, A. & Levine, M. Promoter-proximal tethering elements regulate enhancer-promoter specificity in the Drosophila Antennapedia complex. Proc. Natl Acad. Sci. USA 99, 9243–9247 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Banerji, J., Rusconi, S. & Schaffner, W. Expression of a β-globin gene is enhanced by remote SV40 DNA sequences. Cell 27, 299–308 (1981).
  Article CAS PubMed Google Scholar
• Small, S., Blair, A. & Levine, M. Regulation of even-skipped stripe 2 in the Drosophila embryo. EMBO J. 11, 4047–4057 (1992).
  Article CAS PubMed PubMed Central Google Scholar
• Halfon, M. S. et al. Ras pathway specificity is determined by the integration of multiple signal-activated and tissue-restricted transcription factors. Cell 103, 63–74 (2000).
  Article CAS PubMed Google Scholar
• Yuh, C. H., Ransick, A., Martinez, P., Britten, R. J. & Davidson, E. H. Complexity and organization of DNA-protein interactions in the 5′-regulatory region of an endoderm-specific marker gene in the sea urchin embryo. Mech. Dev. 47, 165–186 (1994).
  Article CAS PubMed Google Scholar
• Sandmann, T. et al. A core transcriptional network for early mesoderm development in Drosophila melanogaster. Genes Dev. 21, 436–449 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Lettice, L. A. et al. Opposing functions of the ETS factor family define Shh spatial expression in limb buds and underlie polydactyly. Dev. Cell 22, 459–467 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Stanojevic, D., Small, S. & Levine, M. Regulation of a segmentation stripe by overlapping activators and repressors in the Drosophila embryo. Science 254, 1385–1387 (1991).
  Article CAS PubMed Google Scholar
• Ip, Y. T., Levine, M. & Small, S. J. The bicoid and dorsal morphogens use a similar strategy to make stripes in the Drosophila embryo. J. Cell Sci. Suppl. 16, 33–38 (1992).
  CAS PubMed Google Scholar
• Xu, X., Yin, Z., Hudson, J. B., Ferguson, E. L. & Frasch, M. Smad proteins act in combination with synergistic and antagonistic regulators to target Dpp responses to the Drosophila mesoderm. Genes Dev. 12, 2354–2370 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Lee, H. H. & Frasch, M. Nuclear integration of positive Dpp signals, antagonistic Wg inputs and mesodermal competence factors during Drosophila visceral mesoderm induction. Development 132, 1429–1442 (2005).
  Article CAS PubMed Google Scholar
• Guss, K. A., Nelson, C. E., Hudson, A., Kraus, M. E. & Carroll, S. B. Control of a genetic regulatory network by a selector gene. Science 292, 1164–1167 (2001).
  Article CAS PubMed Google Scholar
• Mullen, A. C. et al. Master transcription factors determine cell-type-specific responses to TGF-β signaling. Cell 147, 565–576 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Trompouki, E. et al. Lineage regulators direct BMP and Wnt pathways to cell-specific programs during differentiation and regeneration. Cell 147, 577–589 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Sandmann, T. et al. A temporal map of transcription factor activity: mef2 directly regulates target genes at all stages of muscle development. Dev. Cell 10, 797–807 (2006).
  Article CAS PubMed Google Scholar
• Jakobsen, J. S. et al. Temporal ChIP-on-chip reveals Biniou as a universal regulator of the visceral muscle transcriptional network. Genes Dev. 21, 2448–2460 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Cao, Y. et al. Genome-wide MyoD binding in skeletal muscle cells: a potential for broad cellular reprogramming. Dev. Cell 18, 662–674 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Lin, Y. C. et al. A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate. Nature Immunol. 11, 635–643 (2010).
  Article CAS Google Scholar
• Pilon, A. M. et al. Genome-wide ChIP-Seq reveals a dramatic shift in the binding of the transcription factor erythroid Kruppel-like factor during erythrocyte differentiation. Blood 118, e139–e148 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Gaudet, J. & Mango, S. E. Regulation of organogenesis by the Caenorhabditis elegans FoxA protein PHA-4. Science 295, 821–825 (2002).
  Article CAS PubMed Google Scholar
• Wilczynski, B. & Furlong, E. E. Dynamic CRM occupancy reflects a temporal map of developmental progression. Mol. Syst. Biol. 6, 383 (2010).
  Article PubMed PubMed Central Google Scholar
• 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. 25 Apr 2012 (doi:10.1101/gr.132811.111).
  Article CAS PubMed PubMed Central Google Scholar
• Zeitlinger, J. et al. Program-specific distribution of a transcription factor dependent on partner transcription factor and MAPK signaling. Cell 113, 395–404 (2003).
  Article CAS PubMed Google Scholar
• Biggar, S. R. & Crabtree, G. R. Cell signaling can direct either binary or graded transcriptional responses. EMBO J. 20, 3167–3176 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Giorgetti, L. et al. Noncooperative interactions between transcription factors and clustered DNA binding sites enable graded transcriptional responses to environmental inputs. Mol. Cell 37, 418–428 (2010).
  Article CAS PubMed Google Scholar
• Johnson, A. D., Meyer, B. J. & Ptashne, M. Interactions between DNA-bound repressors govern regulation by the lambda phage repressor. Proc. Natl Acad. Sci. USA 76, 5061–5065 (1979).
  Article CAS PubMed PubMed Central Google Scholar
• Lebrecht, D. et al. Bicoid cooperative DNA binding is critical for embryonic patterning in Drosophila. Proc. Natl Acad. Sci. USA 102, 13176–13181 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Zinzen, R. P., Senger, K., Levine, M. & Papatsenko, D. Computational models for neurogenic gene expression in the Drosophila embryo. Curr. Biol. 16, 1358–1365 (2006).
  Article CAS PubMed Google Scholar
• Szymanski, P. & Levine, M. Multiple modes of dorsal-bHLH transcriptional synergy in the Drosophila embryo. EMBO J. 14, 2229–2238 (1995).
  Article CAS PubMed PubMed Central Google Scholar
• Chopra, V. S. & Levine, M. Combinatorial patterning mechanisms in the Drosophila embryo. Brief. Funct. Genomic. Proteomic. 8, 243–249 (2009).
  Article PubMed Google Scholar
• Masel, J. & Siegal, M. L. Robustness: mechanisms and consequences. Trends Genet. 25, 395–403 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Lin, Y. S., Carey, M., Ptashne, M. & Green, M. R. How different eukaryotic transcriptional activators can cooperate promiscuously. Nature 345, 359–361 (1990).
  Article CAS PubMed Google Scholar
• Merika, M., Williams, A. J., Chen, G., Collins, T. & Thanos, D. Recruitment of CBP/p300 by the IFNβ enhanceosome is required for synergistic activation of transcription. Mol. Cell 1, 277–287 (1998).
  Article CAS PubMed Google Scholar
• Voss, T. C. et al. Dynamic exchange at regulatory elements during chromatin remodeling underlies assisted loading mechanism. Cell 146, 544–554 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Miller, J. A. & Widom, J. Collaborative competition mechanism for gene activation in vivo. Mol. Cell. Biol. 23, 1623–1632 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Panne, D., Maniatis, T. & Harrison, S. C. An atomic model of the interferon-β enhanceosome. Cell 129, 1111–1123 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Falvo, J. V., Thanos, D. & Maniatis, T. Reversal of intrinsic DNA bends in the IFNβ gene enhancer by transcription factors and the architectural protein HMG I(Y). Cell 83, 1101–1111 (1995).
  Article CAS PubMed Google Scholar
• Siggers, T., Duyzend, M. H., Reddy, J., Khan, S. & Bulyk, M. L. Non-DNA-binding cofactors enhance DNA-binding specificity of a transcriptional regulatory complex. Mol. Syst. Biol. 7, 555 (2011). This is an interesting study demonstrating that the binding of a cofactor that does not contain a DNA-binding domain can alter the sequence specificity of a transcription factor complex.
  Article CAS PubMed PubMed Central Google Scholar
• Noyes, M. B. et al. Analysis of homeodomain specificities allows the family-wide prediction of preferred recognition sites. Cell 133, 1277–1289 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Carr, A. & Biggin, M. D. A comparison of in vivo and in vitro DNA-binding specificities suggests a new model for homeoprotein DNA binding in Drosophila embryos. EMBO J. 18, 1598–1608 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Slattery, M. et al. Cofactor binding evokes latent differences in DNA binding specificity between hox proteins. Cell 147, 1270–1282 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Liu, X., Lee, C. K., Granek, J. A., Clarke, N. D. & Lieb, J. D. Whole-genome comparison of Leu3 binding in vitro and in vivo reveals the importance of nucleosome occupancy in target site selection. Genome Res. 16, 1517–1528 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Li, X.-y. et al. The role of chromatin accessibility in directing the widespread, overlapping patterns of Drosophila transcription factor binding. Genome Biol. 12, R34 (2011). The authors found that TF occupancy correlates better with DNA accessibility (estimated by DNaseI hypersensitivity) than with predicted sequence affinity, suggesting that this simple property could explain the clustering of TF binding.
  Article CAS PubMed PubMed Central Google Scholar
• John, S. et al. Chromatin accessibility pre-determines glucocorticoid receptor binding patterns. Nature Genet. 43, 264–268 (2011).
  Article CAS PubMed Google Scholar
• Degner, J. F. et al. DNase I sensitivity QTLs are a major determinant of human expression variation. Nature 482, 390–394 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Buck, M. J. & Lieb, J. D. A chromatin-mediated mechanism for specification of conditional transcription factor targets. Nature Genet. 38, 1446–1451 (2006).
  Article CAS PubMed Google Scholar
• Carr, A. & Biggin, M. D. Accessibility of transcriptionally inactive genes is specifically reduced at homeoprotein-DNA binding sites in Drosophila. Nucleic Acids Res. 28, 2839–2846 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• John, S. et al. Interaction of the glucocorticoid receptor with the chromatin landscape. Mol. Cell 29, 611–624 (2008).
  Article CAS PubMed Google Scholar
• Vicent, G. P. et al. Two chromatin remodeling activities cooperate during activation of hormone responsive promoters. PLoS Genet. 5, e1000567 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Hartley, P. D. & Madhani, H. D. Mechanisms that specify promoter nucleosome location and identity. Cell 137, 445–458 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Yarragudi, A., Miyake, T., Li, R. & Morse, R. H. Comparison of ABF1 and RAP1 in chromatin opening and transactivator potentiation in the budding yeast Saccharomyces cerevisiae. Mol. Cell. Biol. 24, 9152–9164 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Workman, J. L. & Kingston, R. E. Nucleosome core displacement in vitro via a metastable transcription factor-nucleosome complex. Science 258, 1780–1784 (1992).
  Article CAS PubMed Google Scholar
• Morse, R. H. Nucleosome disruption by transcription factor binding in yeast. Science 262, 1563–1566 (1993).
  Article CAS PubMed Google Scholar
• Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007).
  Article CAS PubMed Google Scholar
• Kolasinska-Zwierz, P. et al. Differential chromatin marking of introns and expressed exons by H3K36me3. Nature Genet. 41, 376–381 (2009).
  Article CAS PubMed Google Scholar
• Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Heintzman, N. D. et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459, 108–112 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Ernst, J. et al. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473, 43–49 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Heintzman, N. D. & Ren, B. Finding distal regulatory elements in the human genome. Curr. Opin. Genet. Dev. 19, 541–549 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Ong, C. T. & Corces, V. G. Enhancer function: new insights into the regulation of tissue-specific gene expression. Nature Rev. Genet. 12, 283–293 (2011).
  Article CAS PubMed Google Scholar
• Creyghton, M. P. et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc. Natl Acad. Sci. USA 107, 21931–21936 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Rada-Iglesias, A. et al. A unique chromatin signature uncovers early developmental enhancers in humans. Nature 470, 279–283 (2011). References 71 and 72 identified a strong correlation between the presence of H3K27ac on cis -regulatory elements and the activity of the neighbouring gene, providing the first indication that this mark, rather than H3K4me1, is a good indicator of active regulatory elements.
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime _cis_-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• McManus, S. et al. The transcription factor Pax5 regulates its target genes by recruiting chromatin-modifying proteins in committed B cells. EMBO J. 30, 2388–2404 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Ghisletti, S. et al. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. Immunity 32, 317–328 (2010).
  Article CAS PubMed Google Scholar
• Mercer, E. M. et al. Multilineage priming of enhancer repertoires precedes commitment to the B and myeloid cell lineages in hematopoietic progenitors. Immunity 35, 413–425 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Flames, N. & Hobert, O. Gene regulatory logic of dopamine neuron differentiation. Nature 458, 885–889 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Zinzen, R. P., Girardot, C., Gagneur, J., Braun, M. & Furlong, E. E. Combinatorial binding predicts spatio-temporal _cis_-regulatory activity. Nature 462, 65–70 (2009).
  Article CAS PubMed Google Scholar
• Brody, T. et al. Use of a Drosophila genome-wide conserved sequence database to identify functionally related _cis_-regulatory enhancers. Dev. Dyn. 241, 169–189 (2012).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Narlikar, L. et al. Genome-wide discovery of human heart enhancers. Genome Res. 20, 381–392 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Senger, K. et al. Immunity regulatory DNAs share common organizational features in Drosophila. Mol. Cell 13, 19–32 (2004).
  Article CAS PubMed Google Scholar
• Swanson, C. I., Evans, N. C. & Barolo, S. Structural rules and complex regulatory circuitry constrain expression of a Notch- and EGFR-regulated eye enhancer. Dev. Cell 18, 359–370 (2010). By carrying out an extensive mutagenesis analysis, this elegant study found that the sequence of a D. melanogaster enhancer is highly constrained, with the presence and relative positioning of almost all sequence motifs being essential for some aspect of the enhancer's activity. Interestingly, in other Drosophila species, the homologous enhancer adopted different 'solutions' to give the same activity.
  Article CAS PubMed PubMed Central Google Scholar
• Thanos, D. & Maniatis, T. Virus induction of human IFNβ gene expression requires the assembly of an enhanceosome. Cell 83, 1091–1100 (1995).
  Article CAS PubMed Google Scholar
• Merika, M. & Thanos, D. Enhanceosomes. Curr. Opin. Genet. Dev. 11, 205–208 (2001).
  Article CAS PubMed Google Scholar
• Kulkarni, M. M. & Arnosti, D. N. Information display by transcriptional enhancers. Development 130, 6569–6575 (2003).
  Article CAS PubMed Google Scholar
• Arnosti, D. N. & Kulkarni, M. M. Transcriptional enhancers: intelligent enhanceosomes or flexible billboards? J. Cell. Biochem. 94, 890–898 (2005).
  Article CAS Google Scholar
• Brown, C. D., Johnson, D. S. & Sidow, A. Functional architecture and evolution of transcriptional elements that drive gene coexpression. Science 317, 1557–1560 (2007).
  Article CAS PubMed Google Scholar
• Liberman, L. M. & Stathopoulos, A. Design flexibility in _cis_-regulatory control of gene expression: synthetic and comparative evidence. Dev. Biol. 327, 578–589 (2009).
  Article CAS PubMed Google Scholar
• Junion, G. et al. A transcription factor collective defines cardiac cell fate and reflects lineage history. Cell 148, 473–486 (2012).
  Article CAS PubMed Google Scholar
• Gao, F., Foat, B. C. & Bussemaker, H. J. Defining transcriptional networks through integrative modeling of mRNA expression and transcription factor binding data. BMC Bioinformatics 5, 31 (2004).
  Article PubMed PubMed Central Google Scholar
• Ucar, D., Beyer, A., Parthasarathy, S. & Workman, C. T. Predicting functionality of protein-DNA interactions by integrating diverse evidence. Bioinformatics 25, i137–i144 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Krejci, A., Bernard, F., Housden, B. E., Collins, S. & Bray, S. J. Direct response to Notch activation: signaling crosstalk and incoherent logic. Sci. Signal. 2, ra1 (2009).
  Article CAS PubMed Google Scholar
• Zaret, K. S. & Carroll, J. S. Pioneer transcription factors: establishing competence for gene expression. Genes Dev. 25, 2227–2241 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Biswas, A. K. & Johnson, D. G. Transcriptional and nontranscriptional functions of E2F1 in response to DNA damage. Cancer Res. 72, 13–17 (2012).
  Article CAS PubMed Google Scholar
• 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 (2012). The authors tagged a transcription factor with two different tags and carried out a competitive ChIP assay to measure how long it took for the newly transcribed tagged TF to outcompete its alternatively tagged counterpart for chromatin binding. The resulting information provides a nice way to measure TF residence time on each site throughout the genome, which seems to be a better indicator of functional binding events than static occupancy data.
  Article CAS PubMed PubMed Central Google Scholar
• Tagoh, H. et al. Epigenetic silencing of the c-fms locus during B-lymphopoiesis occurs in discrete steps and is reversible. EMBO J. 23, 4275–4285 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Krysinska, H. et al. A two-step, PU.1-dependent mechanism for developmentally regulated chromatin remodeling and transcription of the c-fms gene. Mol. Cell. Biol. 27, 878–887 (2007).
  Article CAS PubMed Google Scholar
• Almer, A., Rudolph, H., Hinnen, A. & Horz, W. Removal of positioned nucleosomes from the yeast PHO5 promoter upon PHO5 induction releases additional upstream activating DNA elements. EMBO J. 5, 2689–2696 (1986).
  Article CAS PubMed PubMed Central Google Scholar
• Biddie, S. C. et al. Transcription factor AP1 potentiates chromatin accessibility and glucocorticoid receptor binding. Mol. Cell 43, 145–155 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• de la Serna, I. L. et al. MyoD targets chromatin remodeling complexes to the myogenin locus prior to forming a stable DNA-bound complex. Mol. Cell. Biol. 25, 3997–4009 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Lupien, M. et al. FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Cell 132, 958–970 (2008). This study shows that FOXA1 occupancy correlates with the prior presence of H3K4me2 at specific enhancer elements. This histone modification directs FOXA1 to induce further chromatin remodelling and TF occupancy specifically at those enhancers. This suggests that even what is perceived as a pioneer factor requires a prior chromatin context.
  Article CAS PubMed PubMed Central Google Scholar
• Siersbæk, R. et al. Extensive chromatin remodelling and establishment of transcription factor 'hotspots' during early adipogenesis. EMBO J. 30, 1459–1472 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Liber, D. et al. Epigenetic priming of a pre-B cell-specific enhancer through binding of Sox2 and Foxd3 at the ESC stage. Cell Stem Cell 7, 114–126 (2010).
  Article CAS PubMed Google Scholar
• Xu, J. et al. Transcriptional competence and the active marking of tissue-specific enhancers by defined transcription factors in embryonic and induced pluripotent stem cells. Genes Dev. 23, 2824–2838 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Hoogenkamp, M. et al. Early chromatin unfolding by RUNX1: a molecular explanation for differential requirements during specification versus maintenance of the hematopoietic gene expression program. Blood 114, 299–309 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Nien, C. Y. et al. Temporal coordination of gene networks by Zelda in the early Drosophila embryo. PLoS Genet. 7, e1002339 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Harrison, M. M., Li, X.-y., Kaplan, T., Botchan, M. R. & Eisen, M. B. Zelda binding in the early Drosophila melanogaster embryo marks regions subsequently activated at the maternal-to-zygotic transition. PLoS Genet. 7, e1002266 (2011). References 109 and 110 indicate that Zelda is a major global regulator of the MZT in D. melanogaster . Zelda binds to thousands of regulatory elements prior to the MZT and prior to the occupancy of other known factors and is required for the zygotic gene activation of a large number of genes.
  Article CAS PubMed PubMed Central Google Scholar
• Struffi, P. et al. Combinatorial activation and concentration-dependent repression of the Drosophila even skipped stripe 3 + 7 enhancer. Development 138, 4291–4299 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Bell, O., Tiwari, V. K., Thoma, N. H. & Schubeler, D. Determinants and dynamics of genome accessibility. Nature Rev. Genet. 12, 554–564 (2011).
  Article CAS PubMed Google Scholar
• Xu, J. et al. Pioneer factor interactions and unmethylated CpG dinucleotides mark silent tissue-specific enhancers in embryonic stem cells. Proc. Natl Acad. Sci. USA 104, 12377–12382 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Serandour, A. A. et al. Epigenetic switch involved in activation of pioneer factor FOXA1-dependent enhancers. Genome Res. 21, 555–565 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Stadler, M. B. et al. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature 480, 490–495 (2011).
  CAS PubMed Google Scholar
• Pevny, L. & Placzek, M. SOX genes and neural progenitor identity. Curr. Opin. Neurobiol. 15, 7–13 (2005).
  Article CAS PubMed Google Scholar
• Olson, E. N. & Klein, W. H. bHLH factors in muscle development: dead lines and commitments, what to leave in and what to leave out. Genes Dev. 8, 1–8 (1994).
  Article CAS PubMed Google Scholar
• Bergsland, M. et al. Sequentially acting Sox transcription factors in neural lineage development. Genes Dev. 25, 2453–2464 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Cui, K. et al. Chromatin signatures in multipotent human hematopoietic stem cells indicate the fate of bivalent genes during differentiation. Cell Stem Cell 4, 80–93 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Watts, J. A. et al. Study of FoxA pioneer factor at silent genes reveals Rfx-repressed enhancer at Cdx2 and a potential indicator of esophageal adenocarcinoma development. PLoS Genet. 7, e1002277 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Hong, J. W., Hendrix, D. A. & Levine, M. S. Shadow enhancers as a source of evolutionary novelty. Science 321, 1314 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Barolo, S. Shadow enhancers: frequently asked questions about distributed _cis_-regulatory information and enhancer redundancy. Bioessays 34, 135–141 (2012).
  Article CAS PubMed Google Scholar
• Frankel, N. et al. Phenotypic robustness conferred by apparently redundant transcriptional enhancers. Nature 466, 490–493 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Perry, M. W., Boettiger, A. N., Bothma, J. P. & Levine, M. Shadow enhancers foster robustness of Drosophila gastrulation. Curr. Biol. 20, 1562–1567 (2010). Developmental genes often have multiple enhancers that seem to have overlapping activities and functions under normal developmental conditions. References 124 and 125 showed that the removal of one (or both) of the enhancers leads to developmental defects when the environmental conditions are more extreme, indicating that 'shadow' enhancers provide robustness to gene expression in the midst of fluctuating environmental temperatures.
  Article CAS PubMed PubMed Central Google Scholar
• Barolo, S. & Levine, M. hairy mediates dominant repression in the Drosophila embryo. EMBO J. 16, 2883–2891 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Perry, M. W., Boettiger, A. N. & Levine, M. Multiple enhancers ensure precision of gap gene-expression patterns in the Drosophila embryo. Proc. Natl Acad. Sci. USA 108, 13570–13575 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Yao, L.-C. et al. Multiple modular promoter elements drive graded brinker expression in response to the Dpp morphogen gradient. Development 135, 2183–2192 (2008).
  Article CAS PubMed Google Scholar
• Prazak, L., Fujioka, M. & Gergen, J. P. Non-additive interactions involving two distinct elements mediate sloppy-paired regulation by pair-rule transcription factors. Dev. Biol. 344, 1048–1059 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Spitz, F., Gonzalez, F. & Duboule, D. A global control region defines a chromosomal regulatory landscape containing the HoxD cluster. Cell 113, 405–417 (2003).
  Article CAS PubMed Google Scholar
• Gonzalez, F., Duboule, D. & Spitz, F. Transgenic analysis of Hoxd gene regulation during digit development. Dev Biol. 306, 847–859 (2007).
  Article CAS PubMed Google Scholar
• Montavon, T. et al. A regulatory archipelago controls Hox genes transcription in digits. Cell 147, 1132–1145 (2011). Genetic and transgenic analyses showed that mouse HoxD genes are controlled by many remote regulatory elements that are separated by large distances. Chromatin conformation capture experiments revealed that these elements come together in cells where they contribute to HoxD gene expression, providing a three-dimensional view of the complex folding of regulatory landscapes during embryonic development.
  Article CAS PubMed Google Scholar
• Suter, D. M. et al. Mammalian genes are transcribed with widely different bursting kinetics. Science 332, 472–474 (2011).
  Article CAS PubMed Google Scholar
• 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 (2008).
  Article CAS PubMed Google Scholar
• 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. Development 133, 761–772 (2006).
  Article CAS PubMed Google Scholar
• Leddin, M. et al. Two distinct auto-regulatory loops operate at the PU.1 locus in B cells and myeloid cells. Blood 117, 2827–2838 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Jack, J. & DeLotto, Y. Structure and regulation of a complex locus: the cut gene of Drosophila. Genetics 139, 1689–1700 (1995).
  CAS PubMed PubMed Central Google Scholar
• Wunderle, V. M., Critcher, R., Hastie, N., Goodfellow, P. N. & Schedl, A. Deletion of long-range regulatory elements upstream of SOX9 causes campomelic dysplasia. Proc. Natl Acad. Sci. USA 95, 10649–10654 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Sagai, T., Hosoya, M., Mizushina, Y., Tamura, M. & Shiroishi, T. Elimination of a long-range _cis_-regulatory module causes complete loss of limb-specific Shh expression and truncation of the mouse limb. Development 132, 797–803 (2005).
  Article CAS PubMed Google Scholar
• Visel, A., Rubin, E. M. & Pennacchio, L. A. Genomic views of distant-acting enhancers. Nature 461, 199–205 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Splinter, E. & de Laat, W. The complex transcription regulatory landscape of our genome: control in three dimensions. EMBO J. 30, 4345–4355 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Butler, J. E. & Kadonaga, J. T. Enhancer-promoter specificity mediated by DPE or TATA core promoter motifs. Genes Dev. 15, 2515–2519 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Zuniga, A. et al. Mouse limb deformity mutations disrupt a global control region within the large regulatory landscape required for Gremlin expression. Genes Dev. 18, 1553–1564 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Cajiao, I., Zhang, A., Yoo, E. J., Cooke, N. E. & Liebhaber, S. A. Bystander gene activation by a locus control region. EMBO J. 23, 3854–3863 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Lower, K. M. et al. Adventitious changes in long-range gene expression caused by polymorphic structural variation and promoter competition. Proc. Natl Acad. Sci. USA 106, 21771–21776 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Klopocki, E. et al. A microduplication of the long range SHH limb regulator (ZRS) is associated with triphalangeal thumb-polysyndactyly syndrome. J. Med. Genet. 45, 370–375 (2008).
  Article CAS PubMed Google Scholar
• Kurth, I. et al. Duplications of noncoding elements 5′ of SOX9 are associated with brachydactyly-anonychia. Nature Genet. 41, 862–863 (2009).
  Article CAS PubMed Google Scholar
• Dathe, K. et al. Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2. Am. J. Hum. Genet. 84, 483–492 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Cande, J., Goltsev, Y. & Levine, M. S. Conservation of enhancer location in divergent insects. Proc. Natl Acad. Sci. USA 106, 14414–14419 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Mongin, E., Dewar, K. & Blanchette, M. Long-range regulation is a major driving force in maintaining genome integrity. BMC Evol. Biol. 9, 203 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Engstrom, P. G., Ho Sui, S. J., Drivenes, O., Becker, T. S. & Lenhard, B. Genomic regulatory blocks underlie extensive microsynteny conservation in insects. Genome Res. 17, 1898–1908 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Dixon, J. R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Nora, E. P. et al. Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature 485, 381–385 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Ludwig, M. Z., Manu, Kittler, R., White, K. P. & Kreitman, M. Consequences of eukaryotic enhancer architecture for gene expression dynamics, development, and fitness. PLoS Genet. 7, e1002364 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Janssens, H. et al. Quantitative and predictive model of transcriptional control of the Drosophila melanogaster even skipped gene. Nature Genet. 38, 1159–1165 (2006).
  Article CAS PubMed Google Scholar
• Klingler, M., Soong, J., Butler, B. & Gergen, J. P. Disperse versus compact elements for the regulation of runt stripes in Drosophila. Dev. Biol. 177, 73–84 (1996).
  Article CAS PubMed Google Scholar
• MacArthur, S. et al. Developmental roles of 21 Drosophila transcription factors are determined by quantitative differences in binding to an overlapping set of thousands of genomic regions. Genome Biol. 10, R80 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Liu, Y. H. et al. A systematic analysis of Tinman function reveals Eya and JAK-STAT signaling as essential regulators of muscle development. Dev. Cell 16, 280–291 (2009).
  Article CAS PubMed Google Scholar
• Zheng, J. et al. Epistatic relationships reveal the functional organization of yeast transcription factors. Mol. Syst. Biol. 6, 420 (2010).
  Article CAS PubMed PubMed Central Google Scholar