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VEZF1 elements mediate protection from DNA methylation

By Jacqueline Dickson, Humaira Gowher, Ruslan Strogantsev, Miklos Gaszner, Alan Hair, Gary Felsenfeld and Adam G. West

Abstract

There is growing consensus that genome organization and long-range gene regulation involves partitioning of the genome into domains of distinct epigenetic chromatin states. Chromatin insulator or barrier elements are key components of these processes as they can establish boundaries between chromatin states. The ability of elements such as the paradigm β-globin HS4 insulator to block the range of enhancers or the spread of repressive histone modifications is well established. Here we have addressed the hypothesis that a barrier element in vertebrates should be capable of defending a gene from silencing by DNA methylation. Using an established stable reporter gene system, we find that HS4 acts specifically to protect a gene promoter from de novo DNA methylation. Notably, protection from methylation can occur in the absence of histone acetylation or transcription. There is a division of labor at HS4; the sequences that mediate protection from methylation are separable from those that mediate CTCF-dependent enhancer blocking and USF-dependent histone modification recruitment. The zinc finger protein VEZF1 was purified as the factor that specifically interacts with the methylation protection elements. VEZF1 is a candidate CpG island protection factor as the G-rich sequences bound by VEZF1 are frequently found at CpG island promoters. Indeed, we show that VEZF1 elements are sufficient to mediate demethylation and protection of the APRT CpG island promoter from DNA methylation. We propose that many barrier elements in vertebrates will prevent DNA methylation in addition to blocking the propagation of repressive histone modifications, as either process is sufficient to direct the establishment of an epigenetically stable silent chromatin stat

Publisher: Public Library of Science
Year: 2010
OAI identifier: oai:eprints.gla.ac.uk:36517
Provided by: Enlighten

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Citations

  1. (1993). A 59 element of the chicken betaglobin domain serves as an insulator in human erythroid cells and protects against position effect in Drosophila. doi
  2. (1991). A position-effect assay for boundaries of higher order chromosomal domains. doi
  3. (1988). An erythrocyte-specific protein that binds to the poly(dG) region of the chicken beta-globin gene promoter. doi
  4. (1999). An insulator element and condensed chromatin region separate the chicken beta-globin locus from an independently regulated erythroid-specific folate receptor gene. doi
  5. (2008). An integrated resource for genome-wide identification and analysis of human tissuespecific differentially methylated regions (tDMRs). doi
  6. (2004). Barrier proteins remodel and modify chromatin to restrict silenced domains. doi
  7. (2008). Bird A
  8. (1997). Characterization of the chicken betaglobin insulator.
  9. (2006). Chromatin insulators. doi
  10. (2001). Chromosomal DNA demethylation specified by protein binding. doi
  11. (2008). Cohesin mediates transcriptional insulation by CCCTC-binding factor. doi
  12. (2004). CpG island methylator phenotype in cancer. doi
  13. (1989). Developmental modulation of protein binding to beta-globin gene regulatory sites within chicken erythrocyte nuclei. doi
  14. (2009). Developmental programming of CpG island methylation profiles in the human genome. doi
  15. (2003). Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. doi
  16. (2002). Gene silencing in mammalian cells and the spread of DNA methylation. doi
  17. (2006). Insulators: exploiting transcriptional and epigenetic mechanisms. doi
  18. (2002). Insulators: many functions, many mechanisms. doi
  19. (1998). Loss of transcriptional activity of a transgene is accompanied by DNA methylation and histone deacetylation and is prevented by insulators. doi
  20. (2005). Methylation of histone H4 by arginine methyltransferase PRMT1 is essential in vivo for many subsequent histone modifications. doi
  21. (1994). Molecular cloning of a novel human cDNA encoding a zinc finger protein that binds to the interleukin-3 promoter. doi
  22. (2002). Position-effect protection and enhancer blocking by the chicken beta-globin insulator are separable activities. doi
  23. (1990). Properties of BGP1, a poly(dG)-binding protein from chicken erythrocytes. doi
  24. (2007). Putative zinc finger protein binding sites are over-represented in the boundaries of methylation-resistant CpG islands in the human genome. doi
  25. (2004). Recruitment of histone modifications by USF proteins at a vertebrate barrier element. doi
  26. (2005). Remote control of gene transcription. doi
  27. (2003). Replication of the chicken betaglobin locus: early-firing origins at the 59 HS4 insulator and the rho- and betaAglobin genes show opposite epigenetic modifications. doi
  28. (2003). Retrovirus silencer blocking by the cHS4 insulator is CTCF independent. doi
  29. (2004). Silencing of transgene transcription precedes methylation of promoter DNA and histone H3 lysine 9. doi
  30. (1994). Sp1 elements protect a CpG island from de novo methylation. doi
  31. (1994). Sp1 sites in the mouse aprt gene promoter are required to prevent methylation of the CpG island. doi
  32. (2006). Spreading of silent chromatin: inaction at a distance. doi
  33. (2002). The barrier function of an insulator couples high histone acetylation levels with specific protection of promoter DNA from methylation. doi
  34. (2002). The chicken beta-globin insulator element conveys chromatin boundary activity but not imprinting at the mouse Igf2/H19 domain.
  35. (2007). The epigenomics of cancer. doi
  36. (1993). The erythroid protein cGATA-1 functions with a stage-specific factor to activate transcription of chromatinassembled beta-globin genes. doi
  37. (1991). The promoter and enhancer o ft h ei n a c t i v ec h i c k e nb e t a - g l o b i ng e n ec o n t a i n sp r e c i s e l yp o s i t i o n e d nucleosomes.
  38. (1999). The protein CTCF is required for the enhancer blocking activity of vertebrate insulators. doi
  39. (2003). The role of DNA methylation in setting up chromatin structure during development. doi
  40. (1980). Tissuespecific DNA cleavages in the globin chromatin domain introduced by DNAase I. doi
  41. (1997). Transcription factor Sp1 is essential for early embryonic development but dispensable for cell growth and differentiation. doi
  42. (2007). USF1 recruits histone modification complexes and is critical for maintenance of a chromatin barrier. doi
  43. (2001). Vezf1/DB1 is an endothelial cell-specific transcription factor that regulates expression of the endothelin-1 promoter. doi
  44. (2007). We gather together: insulators and genome organization. doi

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