Stopped at the border: Boundaries and insulators

Current Opinion in Genetics and Development

Volumn 9, Issue 2, 1999, Pages 191-198

  Bell, Adam C ^a   Felsenfeld, Gary ^a  

^a NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CHROMOSOME PROTEIN;

CELL TRANSFORMATION; CHROMATIN STRUCTURE; DROSOPHILA; HOMEOBOX; OOCYTE; POSITION EFFECT; PRIORITY JOURNAL; REVIEW; TRANSCRIPTION REGULATION;

DROSOPHILA TRITHORAX; VERTEBRATA;

EID: 0033118880     PISSN: 0959437X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-437X(99)80029-X     Document Type: Article

References (49)

1. Hebbes TR, Clayton AL, Thorne AW, Crane-Robinson C: Core histone hyperacetylation co-maps with generalized DNase I sensitivity in the chicken β-globin chromosomal domain. EMBO J 1994, 13:1823-1830.
2. 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. J Mol Biol 1985, 185:341-358.
3. Kellum R, Schedl P: A position-effect assay for boundaries of higher order chromosomal domains. Cell 1991, 64:941-950.
4. Geyer PK, Corces VG: DNA position-specific repression of transcription by a Drosophila zinc finger protein. Genes Dev 1992, 6:1865-1873.
5. 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, 11:1894-1900.
6. Gerasimova TI, Gdula DA, Gerasimov DV, Simonova O, Corces VG: A Drosophila protein that imparts directionality on a chromatin insulator is an enhancer of position-effect variegation. Cell 1995, 82:587-597.
7. Gerasimova TI, Corces VG: Polycomb and trithorax group proteins mediate the function of a chromatin insulator. Cell 1998, 92:511-521. The gene mod(mdg4), together with the DNA binding protein su(Hw), is necessary for insulation by gypsy. This paper shows that mod(mdg4) has characteristics of a trx-G gene, although the fact that it only infrequently co-localizes with trx-G and Pc-G protein sites on polytene chromosomes suggests that it is not a member of trx-G. Mod(mdg4) does co-localize with su(Hw) at all its ∼200 binding sites but there is no evidence of the presence of trx-G or Pc-G proteins at these sites. Nonetheless, trx-G gene mutations enhance, and Pc-G mutations suppress, insulator activity.
8. Roseman RR, Pirrotta V, Geyer PK: The su(Hw) protein insulates expression of the Drosophila melanogaster white gene from chromosomal position-effects. EMBO J 1993, 12:435-442.
9. Kellum R, Schedl P: A group of scs elements function as domain boundaries in an enhancer-blocking assay. Mol Cell Biol 1992, 12:2424-2431.
10. Dunaway M, Hwang JY, Xiong M, Yuen HL: The activity of the scs and scs' insulator elements is not dependent on chromosomal context. Mol Cell Biol 1997,17:182-189.
11. Krebs JE, Dunaway M: The scs and scs' insulator elements impart a cis requirement on enhancer-promoter interactions. Mol Cell 1998, 1:301-308. This paper explores the mechanism of insulation by Drosophila elements scs and scs'. It makes use of dimeric catenanes carrying a reporter on one ring and an enhancer on the other. The enhancer is functional (see reference [12]). When either the promoter or the enhancer is surrounded by scs/scs', however, enhancer-promoter interactions are blocked. These results appear to eliminate a number of proposed mechanisms for insulator action.
12. Dunaway M, Droge P: Transactivation of the Xenopus rRNA gene promoter by its enhancer. Nature 1989, 341:657-659.
13. Cai H, Levine M: Modulation of enhancer-promoter interactions by insulators in the Drosophila embryo. Nature 1995, 376:533-536.
14. Scott KS, Geyer PK: Effects of the su(Hw) insulator protein on the expression of the divergently transcribed Drosophila yolk protein genes. EMBO J 1995, 14:6258-6267.
15. Hagstrom K, Muller M, Schedl P: Fab-7 functions as a chromatin domain boundary to ensure proper segment specification by the Drosophila bithorax complex. Genes Dev 1996, 10:3202-3215.
16. Zhou J, Barolo S, Szymanski P, Levine M: The Fab-7 element of the bithorax complex attenuates enhancer-promoter interactions in the Drosophila embryo. Genes Dev 1996, 10:3195-3201.
17. Mihaly J, Hogga I, Gausz J, Gyurkovics H, Karch F: In situ dissection of the Fab-7 region of the bithorax complex into a chromatin domain boundary and a polycomb-response element. Development 1997, 124:1809-1820. In this report, the Drosophila Fab-7 element is dissected and shown to be composed of a Polycomb response element and a chromatin-domain boundary. The separation of the PRE and insulator activities explains previous contradictory views of Fab-7 function, and enables the study of the insulator properties of the element.
18. Ohtsuki S, Levine M: GAGA mediates the enhancer blocking activity of the eve promoter in the Drosophila embryo. Genes Dev 1998, 12:3325-3330. The authors of this paper report that the eve promoter in Drosophila has enhancer-blocking activity. This activity is shown to depend on binding of the GAGA factor, which is the trithorax-like protein, to a GAGA sequence within the promoter. This connects insulating activity directly to a member of the Trithorax group.
19. Hart CM, Zhao K, Laemmli UK: The scs' boundary element: Characterization of boundary element-associated factors. Mol Cell Biol 1997, 17:999-1009.
20. Zhao K, Hart CM, Laemmli UK: Visualization of chromosomal domains with boundary element-associated factor BEAF-32. Cell 1995, 81:879-889.
21. Cuvier O, Hart CM, Laemmli UK: Identification of a class of chromatin boundary elements. Mol Cell Biol 1998, 18:7478-7486. The authors of this study search for additional binding sites of the protein BEAF-32B, which they had previously shown is associated with scs'. Sites were detected by iterative amplification of bound genomic sequences. Two of the selected sequences are shown to confer position-independent expression on a mini-white reporter gene, dependent on the integrity of the clustered CGATA sequences to which BEAF binds. It seems likely that BEAF binding sites are distributed throughout the Drosophila genome.
22. Cai HN, Levine M: The gypsy insulator can function as a promoter-specific silencer in the Drosophila embryo. EMBO J 1997, 16:1732-1741. The insulating activity of the gypsy retrotransposon requires not only the DNA binding protein suppressor of Hairy wing but also the protein encoded by mod(mdg4). Mutations in mod(mdg4) have different effects on pheno-types induced by gypsy depending upon the gene into which it is inserted. In this paper, synthetic gene complexes carrying two genes-white and eve/lacZ-and driven by distinct enhancers, are separated by the gypsy insulator. In both directions, the enhancer 'outside' the insulator does not work. In mod(mdg4) mutant flies, white is repressed, but lacZ is not. Thus, the effect of the mutation varies with the promoter. Furthermore, repression of white in these mutants cannot involve long-range chromatin structural changes, since lacZ is still active.
23. Mallin DR, Myung JS, Patton JS, Geyer PK: Polycomb group repression is blocked by the Drosophila suppressor of hairy-wing [su(Hw)] insulator. Genetics 1998, 148:331-339. Two genes are placed on either side of a Polycomb response element. One is flanked by su(Hw) binding sites and is protected from PRE repression, the other is not flanked with insulators and is repressed.
24. Strutt H, Cavalli G, Paro R: Co-localization of polycomb protein and GAGA factor on regulatory elements responsible for the maintenance of homeotic gene expression. EMBO J 1997, 16:3621-3632.
25. Morcillo P, Rosen C, Dorsett D: Genes regulating the remote wing margin enhancer in the Drosophila cut locus. Genetics 1996, 144:1143-1154.
26. Morcillo P, Rosen C, Baylies MK, Dorsett D: Chip, a widely expressed chromosomal protein required for segmentation and activity of a remote wing margin enhancer in Drosophila. Genes Dev 1997, 11:2729-2740. Genetic analysis of the Drosophila gene Chip has suggested that it is involved in enhancer-promoter interaction and shown that it is antagonistic to su(Hw) enhancer-blocking activity. The authors clone Chip and show that it is a homolog of recently identified mouse and Xenopus proteins that interact with nuclear LIM domain proteins. The authors suggest that Chip binds with these proteins to stabilize interactions between remote promoters and enhancers, and that su(Hw) functions by interfering with Chip binding.
27. Rippe K, von Hippel PH, Langowski J: Action at a distance: DNA-looping and initiation of transcription. Trends Biochem Sci 1995, 20:500-506.
28. Morris JR, Chen JL, Geyer PK, Wu CT: Two modes of transvection: Enhancer action in trans and bypass of a chromatin insulator in cis. Proc Natl Acad Sci USA 1998, 95:10740-10745.
29. Chung JH, Whiteley M, Felsenfeld G: A 5' element of the chicken β-globin domain serves as an insulator in human erythroid cells and protects against position effect in Drosophila. Cell 1993,74:505-514.
30. Reitman M, Felsenfeld G: Developmental regulation of topoisomerase II sites and DNase I-hypersensitive sites in the chicken β-globin locus. Mol Cell Biol 1990, 10:2774-2786.
31. Chung JH, Bell AC, Felsenfeld G: Characterization of the chicken β-globin insulator. Proc Natl Acad Sci USA 1997, 94:575-580.
32. Pikaart MJ, Recillas-Targa F, Felsenfeld G: Loss of transcriptional activity of a transgene is accompanied by DNA methylation and histone deacetylation and is prevented by insulators. Genes Dev 1998, 12:2852-2862. The chicken β-globin insulator prevents position effects in vertebrate cell lines and is effective in preventing silencing of unselected genes. Silencing is accompanied by deacetylation of the histones in the transgene and promoter methylation. Deacetylation of the transgene chromatin is prevented by insulators. This observation has important implications for models of insulator function.
33. Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A: Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex [see comments]. Nature 1998, 393:386-389.
34. Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N, Strouboulis J, Wolffe AP: Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 1998, 19:187-191.
35. Palla F, Melfi R, Anello L, Di Bernardo M, Spinelli G: Enhancer blocking activity located near the 3′ end of the sea urchin early H2A histone gene. Proc Natl Acad Sci USA 1997, 94:2272-2277. See annotation [37•].
36. Zhong XP, Krangel MS: An enhancer-blocking element between alpha and delta gene segments within the human T cell receptor α/δ locus. Proc Natl Acad Sci USA 1997, 94:5219-5224. See annotation [37•].
37. Robinett CC, O'Connor A, Dunaway M: The repeat organizer, a specialized insulator element within the intergenic spacer of the Xenopus rRNA genes. Mol Cell Biol 1997, 17:2866-2875. These three papers [35•-37•] report the existence of enhancer-blocking elements in loci where differentially regulated genes are closely packed. These and other examples like them add to a growing list of insulators the location of which is suggestive of an in vivo role for enhancer-blocking activity.
38. Wiesendanger B, Lucchini R, Koller T, Sogo JM: Replication fork barriers in the Xenopus rDNA. Nucleic Acids Res 1994, 22:5038-5046.
39. Lu L, Tower J: A transcriptional insulator element, the su(Hw) binding site, protects a chromosomal DNA replication origin from position effects. Mol Cell Biol 1997, 17:2202-2206. See annotation [40•].
40. Greally JM, Starr DJ, Hwang S, Song L, Jaarola M, Zemel S: The mouse H19 locus mediates a transition between imprinted and non-imprinted DNA replication patterns. Hum Mol Genet 1998, 7:91-95. These two reports [39•,40•] are the first to hint that insulators could modulate replication in addition to transcription. See also [37•,38], from which a similar possibility can be inferred.
41. Namciu SJ, Blochlinger KB, Fournier RE: Human matrix attachment regions insulate transgene expression from chromosomal position effects in Drosophila melanogaster. Mol Cell Biol 1998, 18:2382-2391.
42. Nabirochkin S, Ossokina M, Heidmann T: A nuclear matrix/scaffold attachment region co-localizes with the gypsy retrotransposon insulator sequence. J Biol Chem 1998, 273:2473-2479.
43. Wang Y, DeMayo FJ, Tsai SY, O'Malley BW: Ligand-inducible and liver-specific target gene expression in transgenic mice. Nat Biotechnol 1997, 15:239-243.
44. Neff T, Shotkoski F, Stamatoyannopoulos G: Stem cell gene therapy, position effects and chromatin insulators. Stem Cells 1997, 15 (Suppl 1):265-271.
45. Rivella S, Sadelain M: Genetic treatment of severe hemoglobinopathies: The combat against transgene variegation and transgene silencing. Semin Hematol 1998, 35:112-125.
46. Karch F, Galloni M, Sipos L, Gausz J, Gyurkovics H, Schedl P: Mcp and Fab-7: Molecular analysis of putative boundaries of cis-regulatory domains in the bithorax complex of Drosophila melanogaster. Nucleic Acids Res 1994, 22:3138-3146.
47. Leighton PA, Ingram RS, Eggenschwiler J, Efstratiadis A, Tilghman SM: Disruption of imprinting caused by deletion of the H19 gene region in mice. Nature 1995, 375:34-39.
48. Li Q, Stamatoyannopoulos G: Hypersensitive site 5 of the human beta locus control region functions as a chromatin insulator. Blood 1994, 84:1399-1401.
49. Mihaly J, Hogga I, Barges S, Galloni M, Mishra RK, Hagstrom K, Muller M, Schedl P, Sipos L, Gausz J et al.: Chromatin domain boundaries in the bithorax complex. Cell Mol Life Sci 1998, 54:60-70.