Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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The Structure and Function of Locus Control Region

Locus Control Region의 구조와 기능

  • Kim, Ae-Ri (School of Life Sciences, College of Natural Sciences, Pusan National University)
  • 김애리 (부산대학교 자연과학대학 생명과학부)
  • Published : 2007.11.30
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Abstract

Locus control region (LCR) is a cia-acting element which regulates the transcription of genes in developmental stage and/or tissue-specific pattern. Typically, LCR consists of several DNase I hypersensitive sites (HSs), where the binding motifs for transcriptional activators are present. The binding of activators to the HSs recruits chromatin modifying complexes to the LCR, opening chromatin structure and modifying histones covalently through the locus. LCR forms close physical contact with target gene located at a distance by looping away intervening region. In addition, non-coding RNA is transcribed from LCR toward target genes in continuously acetylated active domain. These structural and functional features of LCR suggest that the LCR plays many roles in chromatin activation and transcriptional regulation.

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References

  1. Anderson, J. D., P. T. Lowary and J. Widom. 2001. Effects of histone acetylation on the equilibrium accessibility of nucleosomal DNA target sites. J. Mol. Biol. 307, 977-985. https://doi.org/10.1006/jmbi.2001.4528
  2. Armstrong, J. A. and B. M. Emerson. 1996. NF-E2 disrupts chromatin structure at human b-globin locus control region hypersensitive site 2 in vitro. Mol. Cell. Biol. 16, 5634-5644. https://doi.org/10.1128/MCB.16.10.5634
  3. Baguet, A., X. Sun, T. Arroll, A. Krummand M. Bix. 2005. Intergenic transcription is not required in Th2 cells to maintain histone acetylation and transcriptional permissiveness at the Il4-Il13 locus. J. Immunol. 175, 8146-8153. https://doi.org/10.4049/jimmunol.175.12.8146
  4. Bender, M. A., M. Bulger, J. Closeand M. Groudine. 2000. Beta-globin gene switching and DNase I sensitivity of the endogenous beta-globin locus in mice do not require the locus control region. Mol. Cell 5, 387-393. https://doi.org/10.1016/S1097-2765(00)80433-5
  5. Bulger, M., D. Schubeler, M. A. Bender, J. Hamilton, C. M. Farrell, R. C. Hardisonand M. Groudine. 2003. A complex chromatin landscape revealed by patterns of nuclease sensitivity and histone modification within the mouse beta-globin locus. Mol. Cell. Biol. 23, 5234-5244. https://doi.org/10.1128/MCB.23.15.5234-5244.2003
  6. Carter, D., L. Chakalova, C. S. Osborne, Y. F. Daiand P. Fraser. 2002. Long-range chromatin regulatory interactions in vivo. Nat. Genet. 32, 623-626. https://doi.org/10.1038/ng1051
  7. Dean, A. 2006. On a chromosome far, far away: LCRs and gene regulation. Trends Genet. 22, 38-45. https://doi.org/10.1016/j.tig.2005.11.001
  8. Driscoll, M. C., C. S. Dobkinand B. P. Alter. 1989. Gamma delta beta-thalassemia due to a de novo mutation deleting the 5' beta-globin gene activation-region hypersensitive sites. Proc. Natl. Acad. Sci. USA 86, 7470-7474. https://doi.org/10.1073/pnas.86.19.7470
  9. Drissen, R., R. J. Palstra, N. Gillemans, E. Splinter, F. Grosveld, S. Philipsenand W. de Laat. 2004. The active spatial organization of the beta-globin locus requires the transcription factor EKLF. Genes Dev. 18, 2485-2490. https://doi.org/10.1101/gad.317004
  10. Forrester, W. C., E. Epner, M. C. Driscoll, T. Enver, M. Brice, T. Papayannopoulou and M. Groudine. 1990. A deletion of the human beta-globin locus activation region causes a major alteration in chromatin structure and replication across the entire beta-globin locus. Genes Dev. 4, 1637-1649. https://doi.org/10.1101/gad.4.10.1637
  11. Forsberg, E. C., K. M. Downs, H. M. Christensen, H. Im, P. A. Nuzziand E. H. Bresnick. 2000. Developmentally dynamic histone acetylation pattern of a tissue-specific chromatin domain. Proc. Natl. Acad. Sci. USA. 97, 14494-14499. https://doi.org/10.1073/pnas.97.26.14494
  12. Garcia-Ramirez, M., C. Rocchiniand J. Ausio. 1995. Modulation of chromatin folding by histone acetylation. J. Biol. Chem. 270, 17923-17928. https://doi.org/10.1074/jbc.270.30.17923
  13. Gribnau, J., K. Diderich, S. Pruzina, R. Calzolariand P. Fraser. 2000. Intergenic transcription and developmental remodeling of chromatin subdomains in the human beta- globin locus. Mol. Cell 5, 377-386. https://doi.org/10.1016/S1097-2765(00)80432-3
  14. Grosveld, F., G. B. van Assendelft, D. R. Greavesand G. Kollias. 1987. Position-independent, high-level expression of the human beta-globin gene in transgenic mice. Cell 51, 975-985. https://doi.org/10.1016/0092-8674(87)90584-8
  15. Ho, Y., F. Elefant, N. Cookeand S. Liebhaber. 2002. A defined locus control region determinant links chromatin domain acetylation with long-range gene activation. Mol. Cell 9, 291-302. https://doi.org/10.1016/S1097-2765(02)00447-1
  16. Ho, Y., F. Elefant, S. A. Liebhaberand N. E. Cooke. 2006. Locus control region transcription plays an active role in long-range gene activation. Mol. Cell 23, 365-375. https://doi.org/10.1016/j.molcel.2006.05.041
  17. Im, H., J. A. Grass, K. D. Johnson, S. Kim, M. E. Boyer, A. N. Imbalzano, J. J. Bieker and E. H. Bresnick. 2005. Chromatin domain activation via GATA-1 utilization of a small subset of dispersed GATA motifs within a broad chromosomal region. Proc. Natl. Acad. Sci. USA 102, 17065-17070. https://doi.org/10.1073/pnas.0506164102
  18. Johnson, K. D., J. A. Grass, M. E. Boyer, C. M. Kiekhaefer, G. A. Blobel, M. J. Weiss and E. H. Bresnick. 2002. Cooperative activities of hematopoietic regulators recruit RNA polymerase II to a tissue-specific chromatin domain. Proc. Natl. Acad. Sci. USA 99, 11760-11765. https://doi.org/10.1073/pnas.192285999
  19. Kim, A.and A. Dean. 2004. Developmental stage differences in chromatin sub-domains of the beta-globin locus. Proc. Natl. Acad. Sci. USA 101, 7028-7033. https://doi.org/10.1073/pnas.0307985101
  20. Kim, A., C. M. Kieferand A. Dean. 2007. Distinctive signatures of histone methylation in transcribed coding and noncoding human {beta}-globin sequences. Mol. Cell. Biol. 27, 1271-1279. https://doi.org/10.1128/MCB.01684-06
  21. Kim, A., S. H. Song, M. Brandand A. Dean. 2007. Nucleosome and transcription activator antagonism at human {beta}-globin locus control region DNase I hypersensitive sites. Nucleic Acids Res. In press.
  22. Kim, A., H. Zhao, I. Ifrimand A. Dean. 2007. Beta-globin intergenic transcription and histone acetylation dependent on an enhancer. Mol. Cell Biol. 27, 2980-2986. https://doi.org/10.1128/MCB.02337-06
  23. Kim, S. I., S. J. Bultman, H. Jing, G. A. Blobel and E. H. Bresnick. 2007. Dissecting molecular steps in chromatin domain activation during hematopoietic differentiation. Mol. Cell Biol. 27, 4551-4565. https://doi.org/10.1128/MCB.00235-07
  24. Letting, D. L., C. Rakowski, M. J. Weissand G. A. Blobel. 2003. Formation of a tissue-specific histone acetylation pattern by the hematopoietic transcription factor GATA-1. Mol. Cell Biol. 23, 1334-1340. https://doi.org/10.1128/MCB.23.4.1334-1340.2003
  25. Li, Q., G. Barkessand H. Qian. 2006. Chromatin looping and the probability of transcription. Trends Genet. 22, 197-202. https://doi.org/10.1016/j.tig.2006.02.004
  26. Li, Q., K. R. Peterson, X. Fangand G. Stamatoyannopoulos. 2002. Locus control regions. Blood 100, 3077-3086. https://doi.org/10.1182/blood-2002-04-1104
  27. Ling, J., B. Baibakov, W. Pi, B. M. Emersonand D. Tuan. 2005. The HS2 enhancer of the beta-globin locus control region initiates synthesis of non-coding, polyadenylated RNAs independent of a cis-linked globin promoter. J. Mol. Biol. 350, 883-896. https://doi.org/10.1016/j.jmb.2005.05.039
  28. Litt, M. D., M. Simpson, F. Recillas-Targa, M. N. Prioleauand G. Felsenfeld. 2001. Transitions in histone acetylation reveal boundaries of three separately regulated neighboring loci. EMBO J. 20, 2224-2235. https://doi.org/10.1093/emboj/20.9.2224
  29. Masternak, K., N. Peyraud, M. Krawczyk, E. Barrasand W. Reith. 2003. Chromatin remodeling and extragenic transcription at the MHC class II locus control region. Nat. Immunol. 4, 132-137. https://doi.org/10.1038/ni883
  30. Milot, E., J. Strouboulis, T. Trimborn, M. Wijgerde, E. de Boer, A. Langeveld, K. Tan-Un, W. Vergeer, N. Yannoutsos, F. Grosveld and P. Fraser. 1996. Heterochromatin effects on the frequency and duration of LCR-mediated gene transcription. Cell 87, 105-114. https://doi.org/10.1016/S0092-8674(00)81327-6
  31. Palstra, R. J., B. Tolhuis, E. Splinter, R. Nijmeijer, F. Grosveld and W. de Laat. 2003. The beta-globin nuclear compartment in development and erythroid differentiation. Nat. Genet. 35, 190-194. https://doi.org/10.1038/ng1244
  32. Patrinos, G. P., M. de Krom, E. de Boer, A. Langeveld, A. M. Imam, J. Strouboulis, W. de Laat and F. G. Grosveld. 2004. Multiple interactions between regulatory regions are required to stabilize an active chromatin hub. Genes Dev. 18, 1495-1509. https://doi.org/10.1101/gad.289704
  33. Ragoczy, T., M. A. Bender, A. Telling, R. Byron and M. Groudine. 2006. The locus control region is required for association of the murine beta-globin locus with engaged transcription factories during erythroid maturation. Genes Dev. 20, 1447-1157. https://doi.org/10.1101/gad.1419506
  34. Reik, A., A. Telling, G. Zitnik, D. Cimbora, E. Epner and M. Groudine. 1998. The locus control region is necessary for gene expression in the human beta-globin locus but not the maintenance of an open chromatin structure in erythroid cells. Mol. Cell Biol. 18, 5992-6000. https://doi.org/10.1128/MCB.18.10.5992
  35. Reinke, H. and W. Horz. 2004. Anatomy of a hypersensitive site. Biochim. Biophys. Acta. 1677, 24-29. https://doi.org/10.1016/j.bbaexp.2003.09.014
  36. Routledge, S. J.and N. J. Proudfoot. 2002. Definition of transcriptional promoters in the human beta globin locus control region. J. Mol. Biol. 323, 601-611. https://doi.org/10.1016/S0022-2836(02)01011-2
  37. Sawado, T., J. Halow, M. A. Bender and M. Groudine. 2003. The beta -globin locus control region (LCR) functions primarily by enhancing the transition from transcription initiation to elongation. Genes Dev. 17, 1009-1018. https://doi.org/10.1101/gad.1072303
  38. Schubeler, D., C. Francastel, D. M. Cimbora, A. Reik, D. I. Martin and M. Groudine. 2000. Nuclear localization and histone acetylation: a pathway for chromatin opening and transcriptional activation of the human beta-globin locus. Genes Dev. 14, 940-950.
  39. Schubeler, D., M. Groudine and M. A. Bender. 2001. The murine beta-globin locus control region regulates the rate of transcription but not the hyperacetylation of histones at the active genes. Proc. Natl. Acad. Sci. USA 98, 11432-11437. https://doi.org/10.1073/pnas.201394698
  40. Shewchuk, B. M., S. L. Asa, N. E. Cooke and S. A. Liebhaber. 1999. Pit-1 binding sites at the somatotrope- specific DNase I hypersensitive sites I, II of the human growth hormone locus control region are essential for in vivo hGH-N gene activation. J. Biol. Chem. 274, 35725-35733. https://doi.org/10.1074/jbc.274.50.35725
  41. Strauss, E. C. and S. H. Orkin. 1992. In vivo protein-DNA interactions at hypersensitive site 3 of the human beta- globin locus control region. Proc. Natl. Acad. Sci. USA 89, 5809-5813
  42. Tolhuis, B., R. J. Palstra, E. Splinter, F. Grosveld and W. de Laat. 2002. Looping and interaction between hypersensitive sites in the active b-globin locus. Mol. Cell 10, 1453-1465. https://doi.org/10.1016/S1097-2765(02)00781-5
  43. Vakoc, C. R., D. L. Letting, N. Gheldof, T. Sawado, M. A. Bender, M. Groudine, M. J. Weiss, J. Dekker and G. A. Blobel. 2005. Proximity among distant regulatory elements at the beta-globin locus requires GATA-1 and FOG-1. Mol. Cell 17, 453-462. https://doi.org/10.1016/j.molcel.2004.12.028
  44. Zhao, H.and A. Dean. 2004. An insulator blocks spreading of histone acetylation and interferes with RNA polymerase II transfer between an enhancer and gene. Nucleic Acids Res. 32, 4903-4919. https://doi.org/10.1093/nar/gkh832
  45. Zhao, H.R. D. Friedman, and R. E. Fournier. 2007. The locus control region activates serpin gene expression through recruitment of liver-specific transcription factors and RNA polymerase II. Mol. Cell Biol. 27, 5286-5295. https://doi.org/10.1128/MCB.00176-07
  46. Zhu, X., J. Ling, L. Zhang, W. Pi, M. Wuand D. Tuan. 2007. A facilitated tracking and transcription mechanism of long-range enhancer function. Nucleic Acids Res. 35, 5532-5544. https://doi.org/10.1093/nar/gkm595