ABSTRACT
The eukaryotic genome is organized into functionally and structurally distinct domains, representing regulatory units for gene expression and chromosome behavior. DNA sequences that mark the border between adjacent domains are the insulators or boundary elements, which are required in maintenance of the function of different domains. Some insulators need others enable to play insulation activity. Chromatin domains are defined by distinct sets of post-translationally modified histones. Recent studies show that these histone modifications are also involved in establishment of sharp chromatin boundaries in order to prevent the spreading of distinct domains. Additionally, in some loci, the high-order chromatin structures for long-range looping interactions also have boundary activities, suggesting a correlation between insulators and chromatin loop domains. In this review, we will discuss recent progress in the field of chromatin domain boundaries.
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References
Xin L, Liu DP, Ling CC . A hypothesis for chromatin domain opening. Bioessays 2003; 25:507–14
Felsenfeld G, Groudine M . Controlling the double helix. Nature 2003; 421:448–53
Wei GH, Liu DP, Liang CC . Charting gene regulatory networks: strategies, challenges and perspectives. Biochem J 2004; 381:1–12
Gilbert N, Boyle S, Fiegler H, et al. Chromatin architecture of the human genome: gene-rich domains are enriched in open chromatin fibers. Cell 2004; 118:555–66
Sun FL, Elgin SC . Putting boundaries on silence. Cell 1999; 99:459–62
Capelson M, Corces VG . Boundary elements and nuclear organization. Biol Cell. 2004; 96:617–29
West AG, Gaszner M, Felsenfeld G . Insulators: many functions, many mechanisms. Genes Dev 2002; 16:271–88
West AG, Huang S, Gaszner M, Litt MD, Felsenfeld G . Recruitment of histone modifications by USF proteins at a vertebrate barrier element. Mol Cell 2004; 16:453–63
Ishii K, Arib G, Lin C, Van Houwe G, Laemmli UK . Chromatin boundaries in budding yeast: the nuclear pore connection. Cell 2002; 109:551–62
Shinkura N, Forrester WC . Pushing the envelope: chromatin boundaries at the nuclear pore. Mol Cell 2002; 9:1156–8
Bell AC, West AG, Felsenfeld G . Insulators and boundaries: versatile regulatory elements in the eukaryotic genome. Science 2001; 291:447–50
Zhan HC, Liu DP, Liang CC . Insulator: from chromatin domain boundary to gene regulation. Hum Genet 2001; 109:471–8
Kuhn EJ, Geyer PK . Genomic insulators: connecting properties to mechanism. Curr Opin Cell Biol 2003; 15:259–65
Muravyova E, Golovnin A, Gracheva E, et al. Loss of insulator activity by paired Su(Hw) chromatin insulators. Science 2001; 291:495–8
Cai HN, Shen P . Effects of cis arrangement of chromatin insulators on enhancer-blocking activity. Science 2001; 291:493–5
Byrd K, Corces VG . Visualization of chromatin domains created by the gypsy insulator of Drosophila. J Cell Biol 2003; 162:565–74
Melnikova L, Juge F, Gruzdeva N, et al. Interaction between the GAGA factor and Mod(mdg4) proteins promotes insulator bypass in Drosophila. Proc Natl Acad Sci U S A. 2004; 101:14806–11
Pai CY, Lei EP, Ghosh D, Corces VG . The centrosomal protein CP190 is a component of the gypsy chromatin insulator. Mol Cell 2004; 16:737–48
Lehmann M . Anything else but GAGA: a nonhistone protein complex reshapes chromatin structure. Trends Genet 2004; 20:15–22
Blanton J, Gaszner M, Schedl P . Protein:protein interactions and the pairing of boundary elements in vivo. Genes Dev 2003; 17:664–75
Kuhn EJ, Hart CM, Geyer PK . Studies of the role of the Drosophila scs and scs' insulators in defining boundaries of a chromosome puff. Mol Cell Biol 2004; 24:1470–80
Bell AC, West AG, Felsenfeld G . The protein CTCF is required for the enhancer blocking activity of vertebrate insulators. Cell 1999; 98:387–96
Ohlsson R, Renkawitz R, Lobanenkov V . CTCF is a uniquely versatile transcription regulator linked to epigenetics and disease. Trends Genet 2001; 17:520–7
Mutskov VJ, Farrell CM, Wade PA, Wolffe AP, Felsenfeld G . The barrier function of an insulator couples high histone acetylation levels with specific protection of promoter DNA from methylation. Genes Dev 2002; 16:1540–54
Mutskov V, Felsenfeld G . Silencing of transgene transcription precedes methylation of promoter DNA and histone H3 lysine 9. EMBO J 2004; 23:138–49
Recillas-Targa F, Valadez-Graham V, Farrell CM . Prospects and implications of using chromatin insulators in gene therapy and transgenesis. Bioessays 2004; 26:796–807
Farrell CM, West AG, Felsenfeld G . Conserved CTCF insulator elements flank the mouse and human beta-globin loci. Mol Cell Biol 2002; 22:3820–31
Kato Y, Sasaki H . Imprinting and looping: epigenetic marks control interactions between regulatory elements. Bioessays 2005; 27:1–4
Lee JT . Molecular links between X-inactivation and autosomal imprinting: X-inactivation as a driving force for the evolution of imprinting? Curr Biol 2003; 13:R242–54
Murrell A, Heeson S, Reik W . Interaction between differentially methylated regions partitions the imprinted genes Igf2 and H19 into parent-specific chromatin loops. Nat Genet 2004; 36:889–93
Fedoriw AM, Stein P, Svoboda P, Schultz RM, Bartolomei MS . Transgenic RNAi reveals essential function for CTCF in H19 gene imprinting. Science 2004; 303:238–40
Yu W, Ginjala V, Pant V, et al. Poly(ADP-ribosyl)ation regulates CTCF-dependent chromatin insulation. Nat Genet 2004; 36:1105–10
Jeong S, Pfeifer K . Shifting insulator boundaries. Nat Genet 2004; 36:1036–7
Mukhopadhyay R, Yu W, Whitehead J, et al. The binding sites for the chromatin insulator protein CTCF map to DNA methylation-free domains genome-wide. Genome Res 2004; 14:1594–602
Filippova GN, Mimi K . Cheng, James M . Moore, et al. Boundaries between chromosomal domains of X inactivation and sscape bind CTCF and lack CpG methylation during early development. Developmental Cell 2005; 8:31–42
Donze D, Kamakaka RT . Braking the silence: how heterochromatic gene repression is stopped in its tracks. Bioessays 2002; 24:344–9
Jenuwein T, Allis CD . Translating the histone code. Science 2001; 293:1074–80
Fischle W, Wang Y, Allis CD . Histone and chromatin cross-talk. Curr Opin Cell Biol 2003; 15:172–83
Litt MD, Simpson M, Recillas-Targa F, Prioleau MN, Felsenfeld G . Transitions in histone acetylation reveal boundaries of three separately regulated neighboring loci. EMBO J 2001; 20:2224–35
Litt MD, Simpson M, Gaszner M, Allis CD, Felsenfeld G . Correlation between histone lysine methylation and developmental changes at the chicken beta-globin locus. Science 2001; 293:2453–5
Zhao H, Dean A . An insulator blocks spreading of histone acetylation and interferes with RNA polymerase II transfer between an enhancer and gene. Nucleic Acids Res 2004; 32:4903–19
Zhou J, Berger SL . Good fences make good neighbors: barrier elements and genomic regulation. Mol Cell 2004; 16:500–2
Fischle W, Wang Y, Allis CD . Binary switches and modification cassettes in histone biology and beyond. Nature 2003; 425:475–9
Oki M, Kamakaka RT . Blockers and barriers to transcription: competing activities? Curr Opin Cell Biol 2002; 14:299–304
Ishii K, Laemmli UK . Structural and dynamic functions establish chromatin domains. Mol Cell 2003; 11:237–48
Misteli T . Spatial positioning; a new dimension in genome function. Cell 2004; 119:153–6
Yusufzai TM, Tagami H, Nakatani Y, Felsenfeld G . CTCF tethers an insulator to subnuclear sites, suggesting shared insulator mechanisms across species. Mol Cell 2004; 13:291–8
Yusufzai TM, Felsenfeld G . The 5'-HS4 chicken β-globin insulator is a CTCF-dependent nuclear matrix-associated element. Proc Natl Acad Sci U S A 2004; 101:8620–4
Lewis A, Murrell A . Genomic imprinting: CTCF protects the boundaries. Curr Biol 2004; 14:R284–6
Tolhuis B, Palstra RJ, Splinter E, Grosveld F, de Laat W . Looping and interaction between hypersensitive sites in the active β-globin locus. Mol Cell 2002; 10:1453–65
Palstra RJ, Tolhuis B, Splinter E, et al. The β-globin nuclear compartment in development and erythroid differentiation. Nat Genet 2003; 35:190–4
de Laat W, Grosveld F . Spatial organization of gene expression: the active chromatin hub. Chromosome Res 2003; 11:447–59
Chambeyron S, Bickmore WA . Does looping and clustering in the nucleus regulate gene expression? Curr Opin Cell Biol 2004; 16:256–62
Grosveld F, van Assendelft GB, Greaves DR, Kollias G . Position-independent, high-level expression of the human β-globin gene in transgenic mice. Cell 1987; 51:975–85
Feng DX, Liu DP, Huang Y, et al. The expression of human α-like globin genes in transgenic mice mediated by bacterial artificial chromosome. Proc Natl Acad Sci U S A 2001; 98:15073–7
Brown KE, Amoils S, Horn JM, et al. Expression of α- and β-globin genes occurs within different nuclear domains in haemopoietic cells. Nat Cell Biol 2001; 3:602–6
Isogai Y, Tjian R . Targeting genes and transcription factors to segregated nuclear compartments. Curr Opin Cell Biol 2003; 15:296–303
Schubeler D, Francastel C, Cimbora DM, et al. Nuclear localization and histone acetylation: a pathway for chromatin opening and transcriptional activation of the human beta-globin locus. Genes Dev 2000; 14:940–50
Hacein-Bey-Abina S, von Kalle C, Schmidt M, et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 2003; 348:255–6
Acknowledgements
We apologize to colleagues whose work is not or only indirectly cited due to space limitations and the scope of the review. This work was supported by the grant from the National Natural Science Foundation of China (No. 30393110).
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WEI, G., LIU, D. & LIANG, C. Chromatin domain boundaries: insulators and beyond. Cell Res 15, 292–300 (2005). https://doi.org/10.1038/sj.cr.7290298
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DOI: https://doi.org/10.1038/sj.cr.7290298
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