Nipped-B, a Drosophila homologue of chromosomal adherins, participates in activation by remote enhancers in the cut and Ultrabithorax genes (original) (raw)

Abstract

How enhancers are able to activate promoters located several kilobases away is unknown. Activation by the wing margin enhancer in the cut gene, located 85 kb from the promoter, requires several genes that participate in the Notch receptor pathway in the wing margin, including scalloped, vestigial, mastermind, Chip, and the Nipped locus. Here we show that Nipped mutations disrupt one or more of four essential complementation groups: l(2)41Ae, l(2)41Af, Nipped-A, and Nipped-B. Heterozygous Nipped mutations modify Notch mutant phenotypes in the wing margin and other tissues, and magnify the effects that mutations in the cis regulatory region of cut have on cut expression. Nipped-A and l(2)41Af mutations further diminish activation by a wing margin enhancer partly impaired by a small deletion. In contrast, Nipped-B mutations do not diminish activation by the impaired enhancer, but increase the inhibitory effect of a gypsy transposon insertion between the enhancer and promoter. Nipped-B mutations also magnify the effect of a gypsy insertion in the Ultrabithorax gene. Gypsy binds the Suppressor of Hairy-wing insulator protein [Su(Hw)] that blocks enhancer-promoter communication. Increased insulation by Su(Hw) in Nipped-B mutants suggests that Nipped-B products structurally facilitate enhancer-promoter communication. Compatible with this idea, Nipped-B protein is homologous to a family of chromosomal adherins with broad roles in sister chromatid cohesion, chromosome condensation, and DNA repair.

Full Text

The Full Text of this article is available as a PDF (664.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Altschul S. F., Madden T. L., Schäffer A. A., Zhang J., Zhang Z., Miller W., Lipman D. J. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 1997 Sep 1;25(17):3389–3402. doi: 10.1093/nar/25.17.3389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bach I., Carrière C., Ostendorff H. P., Andersen B., Rosenfeld M. G. A family of LIM domain-associated cofactors confer transcriptional synergism between LIM and Otx homeodomain proteins. Genes Dev. 1997 Jun 1;11(11):1370–1380. doi: 10.1101/gad.11.11.1370. [DOI] [PubMed] [Google Scholar]
  3. Blair S. S., Brower D. L., Thomas J. B., Zavortink M. The role of apterous in the control of dorsoventral compartmentalization and PS integrin gene expression in the developing wing of Drosophila. Development. 1994 Jul;120(7):1805–1815. doi: 10.1242/dev.120.7.1805. [DOI] [PubMed] [Google Scholar]
  4. Breen J. J., Agulnick A. D., Westphal H., Dawid I. B. Interactions between LIM domains and the LIM domain-binding protein Ldb1. J Biol Chem. 1998 Feb 20;273(8):4712–4717. doi: 10.1074/jbc.273.8.4712. [DOI] [PubMed] [Google Scholar]
  5. Cai H., Levine M. Modulation of enhancer-promoter interactions by insulators in the Drosophila embryo. Nature. 1995 Aug 10;376(6540):533–536. doi: 10.1038/376533a0. [DOI] [PubMed] [Google Scholar]
  6. Cohen S. M. Controlling growth of the wing: vestigial integrates signals from the compartment boundaries. Bioessays. 1996 Nov;18(11):855–858. doi: 10.1002/bies.950181102. [DOI] [PubMed] [Google Scholar]
  7. Couso J. P., Knust E., Martinez Arias A. Serrate and wingless cooperate to induce vestigial gene expression and wing formation in Drosophila. Curr Biol. 1995 Dec 1;5(12):1437–1448. doi: 10.1016/s0960-9822(95)00281-8. [DOI] [PubMed] [Google Scholar]
  8. Diaz-Benjumea F. J., Cohen S. M. Serrate signals through Notch to establish a Wingless-dependent organizer at the dorsal/ventral compartment boundary of the Drosophila wing. Development. 1995 Dec;121(12):4215–4225. doi: 10.1242/dev.121.12.4215. [DOI] [PubMed] [Google Scholar]
  9. Dorsett D. Distance-independent inactivation of an enhancer by the suppressor of Hairy-wing DNA-binding protein of Drosophila. Genetics. 1993 Aug;134(4):1135–1144. doi: 10.1093/genetics/134.4.1135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dorsett D., Viglianti G. A., Rutledge B. J., Meselson M. Alteration of hsp82 gene expression by the gypsy transposon and suppressor genes in Drosophila melanogaster. Genes Dev. 1989 Apr;3(4):454–468. doi: 10.1101/gad.3.4.454. [DOI] [PubMed] [Google Scholar]
  11. Fortini M. E., Artavanis-Tsakonas S. The suppressor of hairless protein participates in notch receptor signaling. Cell. 1994 Oct 21;79(2):273–282. doi: 10.1016/0092-8674(94)90196-1. [DOI] [PubMed] [Google Scholar]
  12. Furuya K., Takahashi K., Yanagida M. Faithful anaphase is ensured by Mis4, a sister chromatid cohesion molecule required in S phase and not destroyed in G1 phase. Genes Dev. 1998 Nov 1;12(21):3408–3418. doi: 10.1101/gad.12.21.3408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Geyer P. K., Corces V. G. DNA position-specific repression of transcription by a Drosophila zinc finger protein. Genes Dev. 1992 Oct;6(10):1865–1873. doi: 10.1101/gad.6.10.1865. [DOI] [PubMed] [Google Scholar]
  14. Geyer P. K., Green M. M., Corces V. G. Tissue-specific transcriptional enhancers may act in trans on the gene located in the homologous chromosome: the molecular basis of transvection in Drosophila. EMBO J. 1990 Jul;9(7):2247–2256. doi: 10.1002/j.1460-2075.1990.tb07395.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Giese K., Cox J., Grosschedl R. The HMG domain of lymphoid enhancer factor 1 bends DNA and facilitates assembly of functional nucleoprotein structures. Cell. 1992 Apr 3;69(1):185–195. doi: 10.1016/0092-8674(92)90129-z. [DOI] [PubMed] [Google Scholar]
  16. Giese K., Kingsley C., Kirshner J. R., Grosschedl R. Assembly and function of a TCR alpha enhancer complex is dependent on LEF-1-induced DNA bending and multiple protein-protein interactions. Genes Dev. 1995 Apr 15;9(8):995–1008. doi: 10.1101/gad.9.8.995. [DOI] [PubMed] [Google Scholar]
  17. Harrison D. A., Gdula D. A., Coyne R. S., Corces V. G. A leucine zipper domain of the suppressor of Hairy-wing protein mediates its repressive effect on enhancer function. Genes Dev. 1993 Oct;7(10):1966–1978. doi: 10.1101/gad.7.10.1966. [DOI] [PubMed] [Google Scholar]
  18. Hartley D. A., Xu T. A., Artavanis-Tsakonas S. The embryonic expression of the Notch locus of Drosophila melanogaster and the implications of point mutations in the extracellular EGF-like domain of the predicted protein. EMBO J. 1987 Nov;6(11):3407–3417. doi: 10.1002/j.1460-2075.1987.tb02664.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Holdridge C., Dorsett D. Repression of hsp70 heat shock gene transcription by the suppressor of hairy-wing protein of Drosophila melanogaster. Mol Cell Biol. 1991 Apr;11(4):1894–1900. doi: 10.1128/mcb.11.4.1894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Jack J. W. Molecular organization of the cut locus of Drosophila melanogaster. Cell. 1985 Oct;42(3):869–876. doi: 10.1016/0092-8674(85)90283-1. [DOI] [PubMed] [Google Scholar]
  21. Jack J., DeLotto Y. Effect of wing scalloping mutations on cut expression and sense organ differentiation in the Drosophila wing margin. Genetics. 1992 Jun;131(2):353–363. doi: 10.1093/genetics/131.2.353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Jurata L. W., Gill G. N. Functional analysis of the nuclear LIM domain interactor NLI. Mol Cell Biol. 1997 Oct;17(10):5688–5698. doi: 10.1128/mcb.17.10.5688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Jurata L. W., Kenny D. A., Gill G. N. Nuclear LIM interactor, a rhombotin and LIM homeodomain interacting protein, is expressed early in neuronal development. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11693–11698. doi: 10.1073/pnas.93.21.11693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Jurata L. W., Pfaff S. L., Gill G. N. The nuclear LIM domain interactor NLI mediates homo- and heterodimerization of LIM domain transcription factors. J Biol Chem. 1998 Feb 6;273(6):3152–3157. doi: 10.1074/jbc.273.6.3152. [DOI] [PubMed] [Google Scholar]
  25. Kao H. Y., Ordentlich P., Koyano-Nakagawa N., Tang Z., Downes M., Kintner C. R., Evans R. M., Kadesch T. A histone deacetylase corepressor complex regulates the Notch signal transduction pathway. Genes Dev. 1998 Aug 1;12(15):2269–2277. doi: 10.1101/gad.12.15.2269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kelley M. R., Kidd S., Deutsch W. A., Young M. W. Mutations altering the structure of epidermal growth factor-like coding sequences at the Drosophila Notch locus. Cell. 1987 Nov 20;51(4):539–548. doi: 10.1016/0092-8674(87)90123-1. [DOI] [PubMed] [Google Scholar]
  27. Kim J., Irvine K. D., Carroll S. B. Cell recognition, signal induction, and symmetrical gene activation at the dorsal-ventral boundary of the developing Drosophila wing. Cell. 1995 Sep 8;82(5):795–802. doi: 10.1016/0092-8674(95)90476-x. [DOI] [PubMed] [Google Scholar]
  28. Kim J., Sebring A., Esch J. J., Kraus M. E., Vorwerk K., Magee J., Carroll S. B. Integration of positional signals and regulation of wing formation and identity by Drosophila vestigial gene. Nature. 1996 Jul 11;382(6587):133–138. doi: 10.1038/382133a0. [DOI] [PubMed] [Google Scholar]
  29. Kim J., Shen B., Rosen C., Dorsett D. The DNA-binding and enhancer-blocking domains of the Drosophila suppressor of Hairy-wing protein. Mol Cell Biol. 1996 Jul;16(7):3381–3392. doi: 10.1128/mcb.16.7.3381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Michaelis C., Ciosk R., Nasmyth K. Cohesins: chromosomal proteins that prevent premature separation of sister chromatids. Cell. 1997 Oct 3;91(1):35–45. doi: 10.1016/s0092-8674(01)80007-6. [DOI] [PubMed] [Google Scholar]
  31. Milán M., Diaz-Benjumea F. J., Cohen S. M. Beadex encodes an LMO protein that regulates Apterous LIM-homeodomain activity in Drosophila wing development: a model for LMO oncogene function. Genes Dev. 1998 Sep 15;12(18):2912–2920. doi: 10.1101/gad.12.18.2912. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Mogila V. A., Ladvishenko A. B., Simonova O. B., Gerasimova T. I. Intragenic suppression: Stalker, a retrovirus-like transposable element, can compensate for a deficiency at the cut locus of Drosophila melanogaster. Genetica. 1992;86(1-3):305–311. doi: 10.1007/BF00133729. [DOI] [PubMed] [Google Scholar]
  33. Morcillo P., Rosen C., Baylies M. K., Dorsett D. Chip, a widely expressed chromosomal protein required for segmentation and activity of a remote wing margin enhancer in Drosophila. Genes Dev. 1997 Oct 15;11(20):2729–2740. doi: 10.1101/gad.11.20.2729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Morcillo P., Rosen C., Dorsett D. Genes regulating the remote wing margin enhancer in the Drosophila cut locus. Genetics. 1996 Nov;144(3):1143–1154. doi: 10.1093/genetics/144.3.1143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Neumann C. J., Cohen S. M. A hierarchy of cross-regulation involving Notch, wingless, vestigial and cut organizes the dorsal/ventral axis of the Drosophila wing. Development. 1996 Nov;122(11):3477–3485. doi: 10.1242/dev.122.11.3477. [DOI] [PubMed] [Google Scholar]
  36. Peifer M., Bender W. The anterobithorax and bithorax mutations of the bithorax complex. EMBO J. 1986 Sep;5(9):2293–2303. doi: 10.1002/j.1460-2075.1986.tb04497.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Ptashne M. How eukaryotic transcriptional activators work. Nature. 1988 Oct 20;335(6192):683–689. doi: 10.1038/335683a0. [DOI] [PubMed] [Google Scholar]
  38. Qian S., Capovilla M., Pirrotta V. Molecular mechanisms of pattern formation by the BRE enhancer of the Ubx gene. EMBO J. 1993 Oct;12(10):3865–3877. doi: 10.1002/j.1460-2075.1993.tb06065.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Rabinow L., Birchler J. A. Interactions of vestigial and scabrous with the Notch locus of Drosophila melanogaster. Genetics. 1990 May;125(1):41–50. doi: 10.1093/genetics/125.1.41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Santero E., Hoover T. R., North A. K., Berger D. K., Porter S. C., Kustu S. Role of integration host factor in stimulating transcription from the sigma 54-dependent nifH promoter. J Mol Biol. 1992 Oct 5;227(3):602–620. doi: 10.1016/0022-2836(92)90211-2. [DOI] [PubMed] [Google Scholar]
  41. Scott K. S., Geyer P. K. Effects of the su(Hw) insulator protein on the expression of the divergently transcribed Drosophila yolk protein genes. EMBO J. 1995 Dec 15;14(24):6258–6267. doi: 10.1002/j.1460-2075.1995.tb00316.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Shoresh M., Orgad S., Shmueli O., Werczberger R., Gelbaum D., Abiri S., Segal D. Overexpression Beadex mutations and loss-of-function heldup-a mutations in Drosophila affect the 3' regulatory and coding components, respectively, of the Dlmo gene. Genetics. 1998 Sep;150(1):283–299. doi: 10.1093/genetics/150.1.283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Simmonds A. J., Liu X., Soanes K. H., Krause H. M., Irvine K. D., Bell J. B. Molecular interactions between Vestigial and Scalloped promote wing formation in Drosophila. Genes Dev. 1998 Dec 15;12(24):3815–3820. doi: 10.1101/gad.12.24.3815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Simon J., Peifer M., Bender W., O'Connor M. Regulatory elements of the bithorax complex that control expression along the anterior-posterior axis. EMBO J. 1990 Dec;9(12):3945–3956. doi: 10.1002/j.1460-2075.1990.tb07615.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Spana C., Corces V. G. DNA bending is a determinant of binding specificity for a Drosophila zinc finger protein. Genes Dev. 1990 Sep;4(9):1505–1515. doi: 10.1101/gad.4.9.1505. [DOI] [PubMed] [Google Scholar]
  46. Takahashi K., Yamada H., Yanagida M. Fission yeast minichromosome loss mutants mis cause lethal aneuploidy and replication abnormality. Mol Biol Cell. 1994 Oct;5(10):1145–1158. doi: 10.1091/mbc.5.10.1145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Taniguchi Y., Furukawa T., Tun T., Han H., Honjo T. LIM protein KyoT2 negatively regulates transcription by association with the RBP-J DNA-binding protein. Mol Cell Biol. 1998 Jan;18(1):644–654. doi: 10.1128/mcb.18.1.644. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Thanos D., Maniatis T. Virus induction of human IFN beta gene expression requires the assembly of an enhanceosome. Cell. 1995 Dec 29;83(7):1091–1100. doi: 10.1016/0092-8674(95)90136-1. [DOI] [PubMed] [Google Scholar]
  49. Valentine G., Wallace Y. J., Turner F. R., Zolan M. E. Pathway analysis of radiation-sensitive meiotic mutants of Coprinus cinereus. Mol Gen Genet. 1995 Apr 20;247(2):169–179. doi: 10.1007/BF00705647. [DOI] [PubMed] [Google Scholar]
  50. Wadman I. A., Osada H., Grütz G. G., Agulnick A. D., Westphal H., Forster A., Rabbitts T. H. The LIM-only protein Lmo2 is a bridging molecule assembling an erythroid, DNA-binding complex which includes the TAL1, E47, GATA-1 and Ldb1/NLI proteins. EMBO J. 1997 Jun 2;16(11):3145–3157. doi: 10.1093/emboj/16.11.3145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Xu T., Rebay I., Fleming R. J., Scottgale T. N., Artavanis-Tsakonas S. The Notch locus and the genetic circuitry involved in early Drosophila neurogenesis. Genes Dev. 1990 Mar;4(3):464–475. doi: 10.1101/gad.4.3.464. [DOI] [PubMed] [Google Scholar]
  52. de Celis J. F., Garcia-Bellido A., Bray S. J. Activation and function of Notch at the dorsal-ventral boundary of the wing imaginal disc. Development. 1996 Jan;122(1):359–369. doi: 10.1242/dev.122.1.359. [DOI] [PubMed] [Google Scholar]