Genomic insulators: Connecting properties to mechanism

Current Opinion in Cell Biology

Volumn 15, Issue 3, 2003, Pages 259-265

  Kuhn, Emily J ^a   Geyer, Pamela K ^a  

^a UNIVERSITY OF IOWA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HISTONE ACETYLTRANSFERASE; NUCLEAR PROTEIN; PROTEIN; PROTEIN SUBUNIT; REGULATOR PROTEIN; TRANSFER RNA;

CHROMATIN STRUCTURE; ENHANCER REGION; EUKARYOTE; GENE CONTROL; GENE FUNCTION; GENE INACTIVATION; GENE LOCUS; GENOME IMPRINTING; GENOMICS; HOUSEKEEPING GENE; HUMAN; MOLECULAR DYNAMICS; NONHUMAN; NUCLEAR PORE COMPLEX; POSITION EFFECT; PRIORITY JOURNAL; PROTEIN DNA BINDING; PROTEIN DOMAIN; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN MOTIF; PROTEIN PROTEIN INTERACTION; REGULATOR GENE; REGULATORY MECHANISM; REVIEW; SILENCER GENE; TRANSCRIPTION INITIATION; TRANSCRIPTION REGULATION; ZINC FINGER MOTIF;

EUKARYOTA;

EID: 0038022782     PISSN: 09550674     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0955-0674(03)00039-5     Document Type: Review

References (69)

1. Dillon N., Festenstein R. Unravelling heterochromatin: competition between positive and negative factors regulates accessibility. Trends Genet. 18:2002;252-258.
2. Grewal S.I., Elgin S.C. Heterochromatin: new possibilities for the inheritance of structure. Curr. Opin. Genet. Dev. 12:2002;178-187.
3. ••], multiple clusters were found, suggesting that eukaryotic genomes are organized into domains of transcriptional activity.
4. ••].
5. ••].
6. ••].
7. Kleinjan D.J., van Heyningen V. Position effect in human genetic disease. Hum. Mol. Genet. 7:1998;1611-1618.
8. Milot E., Fraser P., Grosveld F. Position effects and genetic disease. Trends Genet. 12:1996;123-126.
9. Geyer P.K., Clark I. Protecting against promiscuity: the regulatory role of insulators. Cell Mol. Life Sci. 59:2002;2112-2127.
10. West A.G., Gaszner M., Felsenfeld G. Insulators: many functions, many mechanisms. Genes Dev. 16:2002;271-288.
11. Gerasimova T.I., Corces V.G. Chromatin insulators and boundaries: effects on transcription and nuclear organization. Annu. Rev. Genet. 35:2001;193-208.
12. Cai H., Levine M. Modulation of enhancer-promoter interactions by insulators in the Drosophila embryo. Nature. 376:1995;533-536.
13. 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. 14:1995;6258-6267.
14. Geyer P.K., Corces V.G. DNA position-specific repression of transcription by a Drosophila zinc finger protein. Genes Dev. 6:1992;1865-1873.
15. Cuvier O., Hart C.M., Kas E., Laemmli U.K. Identification of a multicopy chromatin boundary element at the borders of silenced chromosomal domains. Chromosoma. 110:2002;519-531.
16. Bi X. Domains of gene silencing near the left end of chromosome III in Saccharomyces cerevisiae. Genetics. 160:2002;1401-1407.
17. Thr gene requires association of the RNA polymerase III complex and activity of histone acetyltransferases. This study supports a model for anti-silencing that involves recruitment of acetylases.
18. Kanduri C., Fitzpatrick G., Mukhopadhyay R., Kanduri M., Lobanenkov V., Higgins M., Ohlsson R. A differentially methylated imprinting control region within the Kcnq1 locus harbours a methylation-sensitive chromatin insulator. J. Biol. Chem. 277:2002;18106-18110.
19. Conte C., Dastugue B., Vaury C. Coupling of enhancer and insulator properties identified in two retrotransposons modulates their mutagenic impact on nearby genes. Mol. Cell Biol. 22:2002;1767-1777.
20. Farrell C.M., West A.G., Felsenfeld G. Conserved CTCF insulator elements flank the mouse and human beta-globin loci. Mol. Cell Biol. 22:2002;3820-3831.
21. Ishihara K., Sasaki H. An evolutionarily conserved putative insulator element near the 3′ boundary of the imprinted Igf2/H19 domain. Hum. Mol. Genet. 11:2002;1627-1636.
22. Zhao K., Hart C.M., Laemmli U.K. Visualization of chromosomal domains with boundary element-associated factor BEAF-32. Cell. 81:1995;879-889.
23. Spana C., Harrison D.A., Corces V.G. The Drosophila melanogaster suppressor of Hairy-wing protein binds to specific sequences of the gypsy retrotransposon. Genes Dev. 2:1988;1414-1423.
24. Gerasimova T.I., Corces V.G. Polycomb and trithorax group proteins mediate the function of a chromatin insulator. Cell. 92:1998;511-521.
25. Noma K., Allis C.D., Grewal S.I. Transitions in distinct histone H3 methylation patterns at the heterochromatin domain boundaries. Science. 293:2001;1150-1155 This paper reports identification of IR-L and IR-R (inverted repeat, left and right, respectively), boundary elements that flank the mating-type locus in fission yeast. Deletion of IR-L or IR-R allows spreading of histone modifications associated with heterochromatin into adjacent euchromatic regions. These findings demonstrate the link between anti-silencers and chromatin domains.
26. Scott K.C., Taubman A.D., Geyer P.K. Enhancer blocking by the Drosophila gypsy insulator depends upon insulator anatomy and enhancer strength. Genetics. 153:1999;787-798.
27. Recillas-Targa F., Pikaart M.J., Burgess-Beusse B., Bell A.C., Litt M.D., West A.G., Gaszner M., Felsenfeld G. Position-effect protection and enhancer blocking by the chicken beta-globin insulator are separable activities. Proc. Natl. Acad Sci. USA. 99:2002;6883-6888 Dissection of the chicken 5′ HS4 insulator demonstrated that independent elements contribute to enhancer-blocking and protection of transgenes from repressive chromatin effects. CTCF binding sites in 5′ HS4 and three other insulators do not have anti-silencing activity.
28. Bell A.C., West A.G., Felsenfeld G. The protein CTCF is required for the enhancer blocking activity of vertebrate insulators. Cell. 98:1999;387-396.
29. Bi X., Broach J.R. Chromosomal boundaries in S. cerevisiae. Curr. Opin. Genet. Dev. 11:2001;199-204.
30. Donze D., Kamakaka R.T. Braking the silence: how heterochromatic gene repression is stopped in its tracks. Bioessays. 24:2002;344-349.
31. Oki M., Kamakaka R.T. Blockers and barriers to transcription: competing activities? Curr. Opin. Cell Biol. 14:2002;299-304.
32. Moazed D. Common themes in mechanisms of gene silencing. Mol. Cell. 8:2001;489-498.
33. Dhillon N., Kamakaka R.T. Breaking through to the other side: silencers and barriers. Curr. Opin. Genet. Dev. 12:2002;188-192.
34. Gasser S.M., Cockell M.M. The molecular biology of the SIR proteins. Gene. 279:2001;1-16.
35. Fourel G., Revardel E., Koering C.E., Gilson E. Cohabitation of insulators and silencing elements in yeast subtelomeric regions. EMBO J. 18:1999;2522-2537.
36. Donze D., Adams C.R., Rine J., Kamakaka R.T. The boundaries of the silenced HMR domain in Saccharomyces cerevisiae. Genes Dev. 13:1999;698-708.
37. Pryde F.E., Louis E.J. Limitations of silencing at native yeast telomeres. EMBO J. 18:1999;2538-2550.
38. Bi X., Braunstein M., Shei G.J., Broach J.R. The yeast HML I silencer defines a heterochromatin domain boundary by directional establishment of silencing. Proc. Natl. Acad Sci. USA. 96:1999;11934-11939.
39. Fourel G., Boscheron C., Revardel E., Lebrun E., Hu Y.F., Simmen K.C., Muller K., Li R., Mermod N., Gilson E. An activation-independent role of transcription factors in insulator function. EMBO Rep. 2:2001;124-132 This study demonstrated that transcriptional activation domains recapitulate boundary activity when tethered to DNA. Importantly, anti-silencing occurs independently of transcription.
40. Fourel G., Miyake T., Defossez P.A., Li R., Gilson E. General regulatory factors (GRFs) as genome partitioners. J. Biol. Chem. 277:2002;41736-41743 In this report, general transcriptional regulatory factors (GRFs) were analyzed to determine whether this class of proteins contains domains with insulator function. The identification of these domains led to the hypothesis that GRFs are involved in partitioning the yeast genome into independent transcriptional domains.
41. Litt M.D., Simpson M., Recillas-Targa F., Prioleau M.N., Felsenfeld G. Transitions in histone acetylation reveal boundaries of three separately regulated neighboring loci. EMBO J. 20:2001;2224-2235 The authors examined levels of histones H3 and H4 acetylation over the chicken β-globin locus and adjacent regions. A constitutive peak of acetylation is located over the 5′ HS4 insulator, suggesting that this element recruits histone acetyltransferases.
42. ••], by examining patterns of methylation and acetylation of histone H3 over the region encompassing the chicken β-globin locus. Methylation of Lys9 is present throughout transcriptionally inactive regions, whereas methylation of Lys4 correlates with H3 acetylation. These studies show that insulators demarcate domains of chromatin modification.
43. Mutskov V.J., Farrell C.M., Wade P.A., Wolffe A.P., Felsenfeld G. The barrier function of an insulator couples high histone acetylation levels with specific protection of promoter DNA from methylation. Genes Dev. 16:2002;1540-1554 This study examined the level of acetylation associated with transgenes flanked by the chicken 5′ HS4 insulator. The authors propose a model in which 5′ HS4 preserves an acetylated state, allowing transcription factors to bind, which then prevents methylation of the transgene promoter and subsequent silencing.
44. Glover D.M., Leibowitz M.H., McLean D.A., Parry H. Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles. Cell. 81:1995;95-105.
45. Hogga I., Karch F. Transcription through the iab-7 cis-regulatory domain of the bithorax complex interferes with maintenance of Polycomb-mediated silencing. Development. 129:2002;4915-4922.
46. Avramova Z., Tikhonov A. Are scs and scs′ 'neutral' chromatin domain boundaries of the locus? Trends Genet. 15:1999;138-139.
47. Drewell R.A., Bae E., Burr J., Lewis E.B. Transcription defines the embryonic domains of cis-regulatory activity at the Drosophila bithorax complex. Proc. Natl. Acad Sci. USA. 99:2002;16853-16858 Analysis of RNA transcripts in the intergenic region of the bithorax complex showed that transcripts in each regulatory region were discrete. Deletion of an insulator-like element disrupts the limits of the transcriptional domains. These studies link transcription activation and domain definition.
48. rpg can function as a heterochromatin boundary element in yeast. Genes Dev. 13:1999;1089-1101.
49. 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. 99:2002;9243-9247 These authors demonstrate that the Drosophila Sex combs reduced promoter proximal region contains an enhancer tethering element that is required for activation by the T1 enhancer. Placement of this element upstream of a different core promoter confers the ability to capture the T1 enhancer.
50. Fransz P., De Jong J.H., Lysak M., Castiglione M.R., Schubert I. Interphase chromosomes in Arabidopsis are organized as well defined chromocenters from which euchromatin loops emanate. Proc. Natl. Acad Sci. USA. 99:2002;14584-14589.
51. Mahy N.L., Perry P.E., Bickmore W.A. Gene density and transcription influence the localization of chromatin outside of chromosome territories detectable by FISH. J. Cell Biol. 159:2002;753-763.
52. Ishii K., Arib G., Lin C., Van Houwe G., Laemmli U.K. Chromatin boundaries in budding yeast: the nuclear pore connection. Cell. 109:2002;551-562 This paper describes a genetic screen used to identify yeast proteins with boundary activity. These studies identified exportin proteins that form an independent transcriptionally active domain within a silenced region by tethering sequences to the nuclear pore complex. This study illustrates that attachment to the nuclear periphery represents one potential mechanism of insulator function.
53. Ghosh D., Gerasimova T.I., Corces V.G. Interactions between the Su(Hw) and Mod(mdg4) proteins required for gypsy insulator function. EMBO J. 20:2001;2518-2527 This study defined the domains of the Drosophila Su(Hw) and Mod(mdg4) proteins required for gypsy insulator body formation. The authors propose that oligomerization of Mod(mdg4) proteins through BTB domains (named from the three founding proteins, broad complex, tramtrack and bric a brac) forms rosette-like structures that divide chromosomes into loop domains.
54. Gerasimova T.I., Byrd K., Corces V.G. A chromatin insulator determines the nuclear localization of DNA. Mol. Cell. 6:2000;1025-1035.
55. ••] demonstrate that a pair of gypsy insulators inserted between an enhancer and promoter allows the enhancer to activate transcription. The authors propose a model for enhancer blocking in which gypsy insulators interact, forming loop domains that constrain enhancer-promoter interactions.
56. ••].
57. Gause M., Morcillo P., Dorsett D. Insulation of enhancer-promoter communication by a gypsy transposon insert in the Drosophila cut gene: cooperation between suppressor of hairy-wing and modifier of mdg4 proteins. Mol. Cell Biol. 21:2001;4807-4817 Domains of interaction between the gypsy insulator protein, Mod(mdg4), and the putative enhancer facilitator protein Chip were defined. These results extend previous findings that Chip interacts with the Su(Hw) protein [58]. Facilitators are thought to promote transcriptional activation by forming a series of loops that bring the enhancer complex close to the promoter. The authors propose that gypsy insulator proteins block some enhancers by direct association with these facilitator proteins.
58. Torigoi E., Bennani-Baiti I.M., Rosen C., Gonzalez K., Morcillo P., Ptashne M., Dorsett D. Chip interacts with diverse homeodomain proteins and potentiates bicoid activity in vivo. Proc. Natl. Acad Sci. USA. 97:2000;2686-2691.
59. Cai H.N., Zhang Z., Adams J.R., Shen P. Genomic context modulates insulator activity through promoter competition. Development. 128:2001;4339-4347 This study demonstrated that the ability of the gypsy insulator to block enhancer activated transcription is influenced by the relative strengths of neighbouring promoters. An enhancer block is less effective if the downstream promoter is highly competitive in attracting the enhancer. Placement of a strong promoter upstream of the insulator increases effectiveness of the block.
60. Saitoh N., Bell A.C., Recillas-Targa F., West A.G., Simpson M., Pikaart M., Felsenfeld G. Structural and functional conservation at the boundaries of the chicken beta-globin domain. EMBO J. 19:2000;2315-2322.
61. Bell A.C., Felsenfeld G. Methylation of a CTCF-dependent boundary controls imprinted expression of the igf2 gene. Nature. 405:2000;482-485.
62. Hark A.T., Schoenherr C.J., Katz D.J., Ingram R.S., Levorse J.M., Tilghman S.M. CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature. 405:2000;486-489.
63. Kaffer C.R., Grinberg A., Pfeifer K. Regulatory mechanisms at the mouse igf2/h19 locus. Mol. Cell Biol. 21:2001;8189-8196.
64. Chung J.H., Bell A.C., Felsenfeld G. Characterization of the chicken beta-globin insulator. Proc. Natl. Acad Sci. USA. 94:1997;575-580.
65. Filippova G.N., Thienes C.P., Penn B.H., Cho D.H., Hu Y.J., Moore J.M., Klesert T.R., Lobanenkov V.V., Tapscott S.J. CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus. Nat. Genet. 28:2001;335-343 This study demonstrated that the congenital form of myotonic muscular dystrophy is caused in part by loss of a CCCTC-binding-factor-dependent insulator. This insulator is responsible for preventing the inappropriate activation of the DMPK gene by an enhancer for the nearby SIX5 gene.
66. Chao W., Huynh K.D., Spencer R.J., Davidow L.S., Lee J.T. CTCF, a candidate trans-acting factor for X-inactivation choice. Science. 295:2002;345-347 CCCTC-binding factor (CTCF) binding sites were identified within the mammalian choice/imprinting centre. These authors propose that CTCF promotes Tsix expression, perhaps by blocking enhancers from interacting with the Xist promoter.
67. Kaffer C.R., Srivastava M., Park K.Y., Ives E., Hsieh S., Batlle J., Grinberg A., Huang S.P., Pfeifer K. A transcriptional insulator at the imprinted H19/Igf2 locus. Genes Dev. 14:2000;1908-1919.
68. Check E. Regulators split on gene therapy as patient shows signs of cancer. Nature. 419:2002;545-546.
69. Anonymous: Bubble babies and bathwater. Nat Biotechnol 2002, 20:1063.