Abstract
In higher eukaryotes regulation of the expression of genes responsible for the development of the organism is a complex process. Often, a single gene may be regulated in different cells and time intervals with the help of dozens of enhancers and promoters. It has recently become clear that enhancers directly interact with target promoters, and the intervening chromatin loops out. However, the mechanisms that ensure the specificity of long-distance interactions between enhancers and promoters remain unclear. One of the most convenient models for the study of remote interactions between the regulatory elements is the bithorax complex (BX-C) of Drosophila melanogaster. This review describes the regulation of the expression of the BX-C homeotic genes and discusses the existing models that explain the specificity of remote interactions between the enhancers and promoters at this locus.
Similar content being viewed by others
References
Bulger, M. and Groudine, M., Functional and mechanistic diversity of distal transcription enhancers, Cell, 2011, vol. 1, pp. 327–339.
de Laat, W. and Duboule, D., Topology of mammalian developmental enhancers and their regulatory landscapes, Nature, 2013, vol. 502, pp. 499–506.
Wendt, K.S. and Grosveld, F.G., Transcription in the context of the 3D nucleus, Curr. Opin. Genet. Dev., 2014, vol. 25, pp. 62–67.
Maksimenko, O. and Georgiev, P., Mechanisms and proteins involved in long-distance interactions, Front. Genet., 2014, vol. 5, p. 28.
Maeda, R.K. and Karch, F., The bithorax complex of Drosophila an exceptional Hox cluster, Curr. Top. Dev. Biol., 2009, vol. 88, pp. 1–33.
Karch, F., Galloni, M., Sipos, L., et al., Mcp and Fab-7: molecular analysis of putative boundaries of cis-regulatory domains in the bithorax complex of Drosophila melanogaster, Nucleic Acids Res., 1994, vol. 22, pp. 3138–3146.
Hagstrom, K., Muller, M., and Schedl, P., Fab-7 functions as a chromatin domain boundary to ensure proper segment specification by the Drosophila bithorax complex, Genes Dev., 1996, vol. 10, pp. 3202–3215.
Zhou, J., Barolo, S., Szymanski, P., et al., The Fab-7 element of the bithorax complex attenuates enhancerpromoter interactions in the Drosophila embryo, Genes Dev., 1996, vol. 10, pp. 3195–3201.
Barges, S., Mihaly, J., Galloni, M., et al., The Fab-8 boundary defines the distal limit of the bithorax complex iab-7 domain and insulated iab-7 from initiation elements and a PRE in the adjacent iab-8 domain, Development, 2000, vol. 127, pp. 779–790.
Gruzdeva, N., Kyrchanova, O., Parshikov, A., et al., The Mcp element from the bithorax complex contains an insulator that is capable of pairwise interactions and can facilitate enhancer-promoter communication, Mol. Cell. Biol., 2005, vol. 25, pp. 3682–3689.
Schwartz, Y.B. and Pirrotta, V., Polycomb silencing mechanisms and the management of genomic programs, Nat. Rev. Genet., 2007, vol. 8, pp. 9–22.
Kassis, J.A. and Brown, J.L., Polycomb group response elements in Drosophila and vertebrates, Adv. Genet., 2013, vol. 81, pp. 83–118.
Peel, A.D., Chipman, A.D., and Akam, M., Arthropod segmentation: beyond the Drosophila paradigm, Nat. Rev. Genet., 2005, vol. 6, pp. 905–916.
Pankratz, M.J. and Jäckle, H., Making stripes in the Drosophila embryo, Trends Genet., 1990, vol. 6, pp. 287–292.
Small, S. and Levine, M., The initiation of pair-rule stripes in the Drosophila blastoderm, Curr. Opin. Genet. Dev., 1991, vol. 1, pp. 255–260.
Maeda, R.K. and Karch, F., The ABC of the BX-C: the bithorax complex explained, Development, 2006, vol. 133, pp. 1413–1422.
Hughes, C.L. and Kaufman, T.C., Hox genes and the evolution of the arthropod body plan, Evol. Dev., 2002, vol. 4, pp. 459–499.
Lewis, E.B., A gene complex controlling segmentation in Drosophila, Nature, 1978, vol. 276, pp. 565–570.
Mihaly, J., Hogga, I., Barges, S., et al., Chromatin domain boundaries in the Bithorax complex, Cell. Mol. Life Sci., 1998, vol. 54, pp. 60–70.
Castelli-Gair, J. and Akam, M., How the Hox gene Ultrabithorax specifies two different segments: the significance of spatial and temporal regulation within metameres, Development, 1995, vol. 121, no. 9, pp. 2973–2982.
Karch, F., Weiffenbach, B., Peifer, M., et al., The abdominal region of the bithorax complex, Cell, 1985, vol. 43, pp. 81–96.
Karch, F., Bender, W., and Weiffenbach, B., abd-A expression in Drosophila embryos, Genes Dev., 1990, vol. 4, pp. 1573–1587.
Simon, J., Peifer, M., Bender, W., et al., Regulatory elements of the bithorax complex that control expression along the anterior-posterior axis, EMBO J., 1990, vol. 9, pp. 3945–3956.
Gummalla, M., Maeda, R.K., Castro Alvarez, J.J., et al., abd-A regulation by the iab-8 noncoding RNA, PLoS Genet., 2012, vol. 8. e1002720
Maeda, R.K. and Karch, F., Gene expression in time and space: additive vs hierarchical organization of cisregulatory regions, Curr. Opin. Genet. Dev., 2011, vol. 21, pp. 187–193.
Mihaly, J., Barges, S., Sipos, L., et al., Dissecting the regulatory landscape of the Abd-B gene of the bithorax complex, Development, 2006, vol. 133, pp. 2983–2993.
Iampietro, C., Gummalla, M., Mutero, A., et al., Initiator elements function to determine the activity state of BX-C enhancers, PLoS Genet., 2010, vol. 6, no. 12. e1001260
Qian, S., Capovilla, M., and Pirrotta, V., The bx region enhancer, a distant cis-control element of the Drosophila Ubx gene and its regulation by hunchback and other segmentation genes, EMBO J., 1991, vol. 10, no. 6, pp. 1415–1425.
Busturia, A., Wightman, C.D., and Sakonju, S., A silencer is required for maintenance of transcriptional repression throughout Drosophila development, Development, 1997, vol. 124, pp. 4343–4350.
Busturia, A. and Bienz, M., Silencers in abdominal-B, a homeotic Drosophila gene, EMBO J., 1993, vol. 12, pp. 1415–1425.
Bowman, S.K., Deaton, A.M., Domingues, H., et al., H3K27 modifications define segmental regulatory domains in the Drosophila bithorax complex, Elife, 2014, vol. 3. e02833
Mihaly, J., Hogga, I., Gausz, J., et al., In situ dissection of the Fab-7 region of the bithorax complex into a chromatin domain boundary and a Polycomb-response element, Development, 1997, vol. 124, pp. 1809–1820.
Müller, J., Hart, C.M., Francis, N.J., et al., Histone methyltransferase activity of a Drosophila Polycomb group repressor complex, Cell, 2002, vol. 111, pp. 197–208.
Steffen, P.A. and Ringrose, L., What are memories made of? How Polycomb and Trithorax proteins mediate epigenetic memory, Nat. Rev. Mol. Cell Biol., 2014, vol. 15, pp. 340–356.
Schwartz, Y.B. and Pirrotta, V., A new world of Polycombs: unexpected partnerships and emerging functions, Nat. Rev. Genet., 2013, vol. 14, pp. 853–864.
Tie, F., Furuyama, T., Prasad-Sinha, J., et al., The Drosophila Polycomb group proteins ESC and E(Z) are present in a complex containing the histone-binding protein p55 and the histone deacetylase RPD3, Development, 2001, vol. 128, no. 2, pp. 275–286.
Cao, R., Wang, L., Wang, H., et al., Role of histone H3 lysine 27 methylation in Polycomb-group silencing, Science, 2002, vol. 298, pp. 1039–1043.
Czermin, B., Melfi, R., McCabe, D., et al., Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites, Cell, 2002, vol. 111, pp. 185–196.
Tillib, S., Petruk, S., Sedkov, Y., et al., Trithorax- and Polycomb-group response elements within an Ultrabithorax transcription maintenance unit consist of closely situated but separable sequences, Mol. Cell Biol., 1999, vol. 19, no. 7, pp. 5189–5202.
Tie, F., Banerjee, R., Saiakhova, A.R., et al., Trithorax monomethylates histone H3K4 and interacts directly with CBP to promote H3K27 acetylation and antagonize Polycomb silencing, Development, 2014, vol. 141, pp. 1129–1139.
Schuettengruber, B., Ganapathi, M., Leblanc, B., et al., Functional anatomy of Polycomb and Trithorax chromatin landscapes in Drosophila embryos, PLoS Biol., 2009, vol. 7, no. 1. e13
Bantignies, F., Grimaud, C., Lavrov, S., et al., Inheritance of Polycomb-dependent chromosomal interactions in Drosophila, Genes Dev., 2003, vol. 17, pp. 2406–2420.
Maksimenko, O.G., Chetverina, D.A., and Georgiev, P.G., Insulators of higher eukaryotes: properties, mechanisms of action, and role in transcriptional regulation, Russ. J. Genet., 2006, vol. 42, no. 8, pp. 845–857.
Chetverina, D., Aoki, T., Erokhin, M., et al., Making connections: insulators organize eukaryotic chromosomes into independent cis-regulatory networks, BioEssays, 2014, vol. 36, pp. 163–172.
Kyrchanova, O. and Georgiev, P., Chromatin insulators and long-distance interactions in Drosophila, FEBS Lett., 2014, vol. 588, pp. 8–14.
Rodin, S., Kyrchanova, O., Pomerantseva, E., et al., New properties of Drosophila Fab-7 insulator, Genetics, 2007, vol. 177, pp. 113–121.
Smith, S.T., Wickramasinghe, P., Olson, A., et al., Genome wide ChIP-chip analyses reveal important roles for CTCF in Drosophila genome organization, Dev. Biol., 2009, vol. 328, pp. 518–528.
Maksimenko, O., Kyrchanova, O., Bonchuk, A., et al., Highly conserved ENY2/Sus1 protein binds to Drosophila CTCF and is required for barrier activity, Epigenetics, 2014, vol. 9, pp. 1261–1270.
Kyrchanova, O.V. and Georgiev, P.G., Functional interaction between an insulator and a Pc-dependent silencer by the example of the Mcp boundary of the Drosophila melanogaster Abd-B Gene, Russ. J. Genet., 2010, vol. 46, no. 5, pp. 521–529.
Kyrchanova, O.V., Ivlieva, T.A., and Georgiev, P.G., Interacting insulators from the Drosophila melanogaster bithorax complex can form independent expression domains, Russ. J. Genet., 2011, vol. 47, no. 12, pp. 1406–1414.
Kyrchanova, O., Toshchakov, S., Podstreshnaya, Y., et al., Study of the functional interaction between the Fab-7 and Fab-8 boundaries and the upstream promoter region in Drosophila Abd-B gene, Mol. Cell. Biol., 2008, vol. 28, pp. 4188–4195.
Kyrchanova, O., Ivlieva, T., Toshchakov, S., et al., Selective interactions of boundaries with upstream region of Abd-B promoter in Drosophila bithorax complex and role of dCTCF in this process, Nucleic Acids Res., 2011, vol. 39, pp. 3042–3052.
Kyrchanova, O., Chetverina, D., Maksimenko, O., et al., Orientation-dependent interaction between Drosophila insulators is a property of this class of regulatory elements, Nucleic Acids Res., 2008, vol. 36, pp. 7019–7028.
Zhou, J., Ashe, H., Burks, C., et al., Characterization of the transvection mediating region of the Abdominal-B locus in Drosophila, Development, 1999, vol. 126, pp. 3057–3065.
Zhou, J. and Levine, M., A novel cis-regulatory element, the PTS, mediates an anti-insulator activity in the Drosophila embryo, Cell, 1999, vol. 99, pp. 567–575.
Lin, Q., Chen, Q., Lin, L., et al., The promoter targeting sequence mediates epigenetically heritable transcription memory, Genes Dev., 2004, vol. 18, pp. 2639–2651.
Chen, Q., Lin, L., Smith, S., et al., Multiple promoter targeting sequences exist in Abdominal-B to regulate long-range gene activation, Dev. Biol., 2005, vol. 286, pp. 629–636.
Akbari, O.S., Bae, E., Johnsen, H., et al., A novel promoter-tethering element regulates enhancer-driven gene expression at the bithorax complex in the Drosophila embryo, Development, 2008, vol. 135, pp. 123–131.
Kyrchanova, O.V. and Georgiev, P.G., Drosophila Fab-7 insulator from the regulatory domain of the bithorax complex effectively blocks Polycomb-mediated repression in transgenic lines, Russ. J. Genet., 2012, vol. 48, no. 3, pp. 261–267.
Herold, M., Bartkuhn, M., and Renkawitz, R., CTCF: insights into insulator function during development, Development, 2012, vol. 139, pp. 1045–1057.
Moon, H., Filippova, G., Loukinov, D., et al., CTCF is conserved from Drosophila to humans and confers enhancer blocking of the Fab-8 insulator, EMBO Rep., 2005, vol. 2, pp. 165–170.
Holohan, E.E., Kwong, C., Adryan, B., et al., CTCF genomic binding sites in Drosophila and the organization of the bithorax complex, PLoS Genet., 2007, vol. 3, no. 7. e112
Ivlieva, T.A., Georgiev, P.G., and Kyrchanova, O.V., Study of the enhancer-blocking activities of new boundaries in the bithorax complex of Drosophila melanogaster, Russ. J. Genet., 2011, vol. 47, no. 9, pp. 1047–1051.
Mohan, M., Bartkuhn, M., Herold, M., et al., The Drosophila insulator proteins CTCF and CP190 link enhancer blocking to body patterning, EMBO J., 2007, vol. 26, pp. 4203–4214.
Moshkovich, N., Nisha, P., Boyle, P.J., et al., RNAi-independent role for Argonaute2 in CTCF/CP190 chromatin insulator function, Genes Dev., 2011, vol. 25, pp. 1686–1701.
Sexton, T., Yaffe, E., Kenigsberg, E., et al., Three-dimensional folding and functional organization principles of the Drosophila genome, Cell, 2012, vol. 148, pp. 458–472.
Maksimenko, O., Bartkuhn, M., Stakhov, V., et al., Two new insulator proteins, Pita and ZIPIC, target CP190 to chromatin, Genome Res., 2014. pii: gr.174169.114
Kyrchanova, O., Toshchakov, S., Parshikov, A., et al., Study of the functional interaction between Mcp insulators from the Drosophila bithorax complex: effects of insulator pairing on the enhancer-promoter communication, Mol. Cell. Biol., 2007, vol. 27, pp. 3035–3043.
Muller, M., Hangstrom, K., Gyurkovics, H., et al., The Mcp element from the Drosophila melanogaster bithorax complex mediates long-distance regulatory interactions, Genetics, 1999, vol. 153, pp. 1333–1356.
Li, H.B., Muller, M., Bahechar, I.A., et al., Insulators, not Polycomb Response Elements, are required for long-distance interactions between Polycomb targets in Drosophila, Mol. Cell. Biol., 2011, vol. 31, pp. 616–625.
Iampietro, C., Célard, F., Gyurkovics, H., et al., Boundary swapping in the Drosophila bithorax complex, Development, 2008, vol. 135, pp. 3983–3987.
Author information
Authors and Affiliations
Corresponding author
Additional information
Original Russian Text © O.V. Kyrchanova, P.G. Georgiev, 2015, published in Genetika, 2015, Vol. 51, No. 5, pp. 529–538.
Rights and permissions
About this article
Cite this article
Kyrchanova, O.V., Georgiev, P.G. The bithorax complex of Drosophila melanogaster as a model for studying specific long-distance interactions between enhancers and promoters. Russ J Genet 51, 440–448 (2015). https://doi.org/10.1134/S1022795415050038
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S1022795415050038