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Genetic and Epigenetic Mechanisms of β-Globin Gene Switching

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Abstract

Vertebrates have multiple forms of hemoglobin that differ in the composition of their polypeptide chains. During ontogenesis, the composition of these subunits changes. Genes encoding different α- and β-polypeptide chains are located in two multigene clusters on different chromosomes. Each cluster contains several genes that are expressed at different stages of ontogenesis. The phenomenon of stage-specific transcription of globin genes is referred to as globin gene switching. Mechanisms of expression switching, stage-specific activation, and repression of transcription of α- and β-globin genes are of interest from both theoretical and practical points of view. Alteration of balanced expression of globin genes, which usually occurs due to damage to adult β-globin genes, leads to development of severe diseases–hemoglobinopathies. In most cases, reactivation of the fetal hemoglobin gene in patients with β-thalassemia and sickle cell disease can reduce negative consequences of irreversible alterations of expression of the β-globin genes. This review focuses on the current state of research on genetic and epigenetic mechanisms underlying stage-specific switching of β-globin genes.

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Abbreviations

CTCF:

a transcription factor protein

GWAS:

genome-wide association studies

Hb:

hemoglobin

HS:

hypersensitive site

LCR:

locus control region

MBP:

methyl-binding proteins

References

  1. Stamatoyannopoulos, G. (2005) Control of globin gene expression during development and erythroid differentiation, Exp. Hematol., 33, 259–271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wozniak, R. J., and Bresnick, E. H. (2008) Epigenetic control of complex loci during erythropoiesis, Curr. Top. Dev. Biol., 82, 55–83.

    Article  CAS  PubMed  Google Scholar 

  3. Jagannathan-Bogdan, M., and Zon, L. I. (2013) Hematopoiesis, Development, 140, 2463–2467.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Palis, J. (2014) Primitive and definitive erythropoiesis in mammals, Frontiers Physiol., 5, 3.

    Article  Google Scholar 

  5. Vandekerckhove, J., Courtois, G., Coulon, S., Ribeil, J., and Hermine, O. (2009) Regulation of erythropoiesis, in Disorders of Erythropoiesis, Erythrocytes and Iron Metabolism (Beaumont, C., and Brugnara, C., eds.) European School of Haematology, pp. 44–86.

    Google Scholar 

  6. Sankaran, V. G., Xu, J., and Orkin, S. H. (2010) Advances in the understanding of haemoglobin switching, Br. J. Haematol., 149, 181–194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Krivega, I., Byrnes, C., de Vasconcellos, J. F., Lee, Y. T., Kaushal, M., Dean, A., and Miller, J. L. (2015) Inhibition of G9a methyltransferase stimulates fetal hemoglobin production by facilitating LCR/gamma-globin looping, Blood, 126, 665–672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cao, A., and Moi, P. (2002) Regulation of the globin genes, Pediatr. Res., 51, 415–421.

    Article  CAS  PubMed  Google Scholar 

  9. Razin, S. V., Ulianov, S. V., Ioudinkova, E. S., Gushchanskaya, E. S., Gavrilov, A. A., and Iarovaia, O. V. (2012) Domains of alpha-and beta-globin genes in the context of the structural-functional organization of the eukaryotic genome, Biochemistry (Moscow), 77, 1409–1423.

    Article  CAS  Google Scholar 

  10. Ginder, G. D. (2015) Epigenetic regulation of fetal globin gene expression in adult erythroid cells, Transl. Res., 165, 115–125.

    Article  CAS  PubMed  Google Scholar 

  11. Lee, W. S., McColl, B., Maksimovic, J., and Vadolas, J. (2017) Epigenetic interplay at the beta-globin locus, Biochim. Biophys. Acta, 1860, 393–404.

    Article  CAS  Google Scholar 

  12. Palstra, R. J., de Laat, W., and Grosveld, F. (2008) Beta-globin regulation and long-range interactions, Adv. Genetics, 61, 107–142.

    CAS  Google Scholar 

  13. Noordermeer, D., and de aat, W. (2008) Joining the loops: beta-globin gene regulation, IUBMB Life, 60, 824–833.

    Article  CAS  PubMed  Google Scholar 

  14. Breda, L., Motta, I., Lourenco, S., Gemmo, C., Deng, W., Rupon, J. W., Abdulmalik, O. Y., Manwani, D., Blobel, G. A., and Rivella, S. (2016) Forced chromatin looping raises fetal hemoglobin in adult sickle cells to higher levels than pharmacologic inducers, Blood, 128, 1139–1143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sankaran, V. G., and Orkin, S. H. (2013) The switch from fetal to adult hemoglobin, Cold Spring Harb. Perspect. Med., 3, a011643.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Faruqi, M. (2013) Blood disorders: epigenetically enhancing haemoglobin production, Nat. Rev. Drug Discov., 12, 262–263.

    Article  CAS  PubMed  Google Scholar 

  17. Recillas-Targa, F., and Razin, S. V. (2001) Chromatin domains and regulation of gene expression: familiar and enigmatic clusters of chicken globin genes, Crit. Rev. Eukaryot. Gene Expr., 11, 227–242.

    CAS  PubMed  Google Scholar 

  18. Razin, S. V., Farrell, C. M., and Recillas-Targa, F. (2003) Genomic domains and regulatory elements operating at the domain level, Int. Rev. Cytol., 226, 63–125.

    Article  CAS  PubMed  Google Scholar 

  19. Burgess-Beusse, B., Farrell, C., Gaszner, M., Litt, M., Mutskov, V., Recillas-Targa, F., Simpson, M., West, A., and Felsenfeld, G. (2002) The insulation of genes from external enhancers and silencing chromatin, Proc. Natl. Acad. Sci. USA, 99, 16433–16437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hanscombe, O., Whyatt, D., Fraser, P., Yannoutsos, N., Greaves, D., Dillon, N., and Grosveld, F. (1991) Importance of globin gene order for correct developmental expression, Genes Dev., 5, 1387–1394.

    Article  CAS  PubMed  Google Scholar 

  21. Talbot, D., Collis, P., Antoniou, M., Vidal, M., Grosveld, F., and Greaves, D. R. (1989) A dominant control region from the human beta-globin locus conferring integration site-independent gene expression, Nature, 338, 352–355.

    Article  CAS  PubMed  Google Scholar 

  22. Forrester, W. C., Epner, E., Driscoll, M. C., Enver, T., Brice, M., Papayannopoulou, T., and Groudine, M. (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.

    Article  CAS  PubMed  Google Scholar 

  23. Fraser, P., Pruzina, S., Antoniou, M., and Grosveld, F. (1993) Each hypersensitive site of the human beta-globin locus control region confers a different developmental pattern of expression on the globin genes, Genes Dev., 7, 106–113.

    Article  CAS  PubMed  Google Scholar 

  24. Yin, W., Barkess, G., Fang, X., Xiang, P., Cao, H., Stamatoyannopoulos, G., and Li, Q. (2007) Histone acetylation at the human beta-globin locus changes with developmental age, Blood, 110, 4101–4107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Plant, K. E., Routledge, S. J., and Proudfoot, N. J. (2001) Intergenic transcription in the human beta-globin gene cluster, Mol. Cell. Biol., 21, 6507–6514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Miles, J., Mitchell, J. A., Chakalova, L., Goyenechea, B., Osborne, C. S., O’Neill, L., Tanimoto, K., Engel, J. D., and Fraser, P. (2007) Intergenic transcription, cell-cycle and the developmentally regulated epigenetic profile of the human beta-globin locus, PloS One, 2, e630.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Gribnau, J., Diderich, K., Pruzina, S., Calzolari, R., and Fraser, P. (2000) Intergenic transcription and developmental remodeling of chromatin subdomains in the human beta-globin locus, Mol. Cell, 5, 377–386.

    Article  CAS  PubMed  Google Scholar 

  28. Haussecker, D., and Proudfoot, N. J. (2005) Dicer-dependent turnover of intergenic transcripts from the human beta-globin gene cluster, Mol. Cell. Biol., 25, 9724–9733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Trimborn, T., Gribnau, J., Grosveld, F., and Fraser, P. (1999) Mechanisms of developmental control of transcription in the murine alpha-and beta-globin loci, Genes Dev., 13, 112–124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gaensler, K. M., Kitamura, M., and Kan, Y. W. (1993) Germ-line transmission and developmental regulation of a 150-kb yeast artificial chromosome containing the human beta-globin locus in transgenic mice, Proc. Natl. Acad. Sci. USA, 90, 11381–11385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nickol, J. M., and Felsenfeld, G. (1988) Bidirectional control of the chicken beta-and epsilon-globin genes by a shared enhancer, Proc. Natl. Acad. Sci. USA, 85, 2548–2552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bank, A. (2006) Regulation of human fetal hemoglobin: new players, new complexities, Blood, 107, 435–443.

    Article  CAS  PubMed  Google Scholar 

  33. Enver, T., Raich, N., Ebens, A. J., Papayannopoulou, T., Costantini, F., and Stamatoyannopoulos, G. (1990) Developmental regulation of human fetal-to-adult globin gene switching in transgenic mice, Nature, 344, 309–313.

    Article  CAS  PubMed  Google Scholar 

  34. Wijgerde, M., Grosveld, F., and Fraser, P. (1995) Transcription complex stability and chromatin dynamics in vivo, Nature, 377, 209–213.

    Article  CAS  PubMed  Google Scholar 

  35. Deng, W., Rupon, J. W., Krivega, I., Breda, L., Motta, I., Jahn, K. S., Reik, A., Gregory, P. D., Rivella, S., Dean, A., and Blobel, G. A. (2014) Reactivation of developmentally silenced globin genes by forced chromatin looping, Cell, 158, 849–860.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Li, Q., Blau, C. A., Clegg, C. H., Rohde, A., and Stamatoyannopoulos, G. (1998) Multiple epsilon-promoter elements participate in the developmental control of epsilon-globin genes in transgenic mice, J. Biol. Chem., 273, 17361–17367.

    Article  CAS  PubMed  Google Scholar 

  37. Navas, P. A., Peterson, K. R., Li, Q., Skarpidi, E., Rohde, A., Shaw, S. E., Clegg, C. H., Asano, H., and Stamatoyannopoulos, G. (1998) Developmental specificity of the interaction between the locus control region and embryonic or fetal globin genes in transgenic mice with an HS3 core deletion, Mol. Cell. Biol., 18, 4188–4196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Navas, P. A., Peterson, K. R., Li, Q., McArthur, M., and Stamatoyannopoulos, G. (2001) The 5′HS4 core element of the human beta-globin locus control region is required for high-level globin gene expression in definitive but not in primitive erythropoiesis, J. Mol. Biol., 312, 17–26.

    Article  CAS  PubMed  Google Scholar 

  39. Fedosyuk, H., and Peterson, K. R. (2007) Deletion of the human beta-globin LCR 5′HS4 or 5′HS1 differentially affects beta-like globin gene expression in beta-YAC transgenic mice, Blood Cells Mol. Dis., 39, 44–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ashe, H. L., Monks, J., Wijgerde, M., Fraser, P., and Proudfoot, N. J. (1997) Intergenic transcription and transinduction of the human beta-globin locus, Genes Dev., 11, 2494–2509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wong, H., Winn, P. J., and Mozziconacci, J. (2009) A molecular model of chromatin organisation and transcription: how a multi-RNA polymerase II machine transcribes and remodels the beta-globin locus during development, BioEssays, 31, 1357–1366.

    Article  CAS  PubMed  Google Scholar 

  42. Travers, A. (1999) Chromatin modification by DNA tracking, Proc. Natl. Acad. Sci. USA, 96, 13634–13637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Chaturvedi, C. P., Somasundaram, B., Singh, K., Carpenedo, R. L., Stanford, W. L., Dilworth, F. J., and Brand, M. (2012) Maintenance of gene silencing by the coordinate action of the H3K9 methyltransferase G9a/KMT1C and the H3K4 demethylase Jarid1a/KDM5A, Proc. Natl. Acad. Sci. USA, 109, 18845–18850.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Menzel, S., Garner, C., Gut, I., Matsuda, F., Yamaguchi, M., Heath, S., Foglio, M., Zelenika, D., Boland, A., Rooks, H., Best, S., Spector, T. D., Farrall, M., Lathrop, M., and Thein, S. L. (2007) A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15, Nature Genet., 39, 1197–1199.

    Article  CAS  PubMed  Google Scholar 

  45. Nuinoon, M., Makarasara, W., Mushiroda, T., Setianingsih, I., Wahidiyat, P. A., Sripichai, O., Kumasaka, N., Takahashi, A., Svasti, S., Munkongdee, T., Mahasirimongkol, S., Peerapittayamongkol, C., Viprakasit, V., Kamatani, N., Winichagoon, P., Kubo, M., Nakamura, Y., and Fucharoen, S. (2010) A genome-wide association identified the common genetic variants influence disease severity in beta0-thalassemia/hemoglobin E, Hum. Genet., 127, 303–314.

    Article  CAS  PubMed  Google Scholar 

  46. Fell, H. P., Smith, R. G., and Tucker, P. W. (1986) Molecular analysis of the t(2;14) translocation of childhood chronic lymphocytic leukemia, Science, 232, 491–494.

    Article  CAS  PubMed  Google Scholar 

  47. Nakamura, T., Yamazaki, Y., Saiki, Y., Moriyama, M., Largaespada, D. A., Jenkins, N. A., and Copeland, N. G. (2000) Evi9 encodes a novel zinc finger protein that physically interacts with BCL6, a known human B-cell proto-oncogene product, Mol. Cell. Biol., 20, 3178–3186.

    CAS  PubMed  Google Scholar 

  48. Suzuki, T., Shen, H., Akagi, K., Morse, H. C., Malley, J. D., Naiman, D. Q., Jenkins, N. A., and Copeland, N. G. (2002) New genes involved in cancer identified by retroviral tagging, Nat. Genet., 32, 166–174.

    Article  CAS  PubMed  Google Scholar 

  49. Sankaran, V. G., Menne, T. F., Xu, J., Akie, T. E., Lettre, G., Van Handel, B., Mikkola, H. K., Hirschhorn, J. N., Cantor, A. B., and Orkin, S. H. (2008) Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A, Science, 322, 1839–1842.

    Article  CAS  PubMed  Google Scholar 

  50. Sankaran, V. G., Xu, J., Ragoczy, T., Ippolito, G. C., Walkley, C. R., Maika, S. D., Fujiwara, Y., Ito, M., Groudine, M., Bender, M. A., Tucker, P. W., and Orkin, S. H. (2009) Developmental and species-divergent globin switching are driven by BCL11A, Nature, 460, 1093–1097.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Xu, J., Bauer, D. E., Kerenyi, M. A., Vo, T. D., Hou, S., Hsu, Y. J., Yao, H., Trowbridge, J. J., Mandel, G., and Orkin, S. H. (2013) Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A, Proc. Natl. Acad. Sci. USA, 110, 6518–6523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Xu, J., Sankaran, V. G., Ni, M., Menne, T. F., Puram, R. V., Kim, W., and Orkin, S. H. (2010) Transcriptional silencing of gamma-globin by BCL11A involves long-range interactions and cooperation with SOX6, Genes Dev., 24, 783–798.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hagiwara, N. (2011) Sox6, jack of all trades: a versatile regulatory protein in vertebrate development, Dev. Dynamics, 240, 1311–1321.

    CAS  Google Scholar 

  54. Dumitriu, B., Patrick, M. R., Petschek, J. P., Cherukuri, S., Klingmuller, U., Fox, P. L., and Lefebvre, V. (2006) Sox6 cell-autonomously stimulates erythroid cell survival, proliferation, and terminal maturation and is thereby an important enhancer of definitive erythropoiesis during mouse development, Blood, 108, 1198–1207.

    CAS  Google Scholar 

  55. Raich, N., Clegg, C. H., Grofti, J., Romeo, P. H., and Stamatoyannopoulos, G. (1995) GATA1 and YY1 are developmental repressors of the human epsilon-globin gene, EMBO J., 14, 801–809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Alhashem, Y. N., Vinjamur, D. S., Basu, M., Klingmuller, U., Gaensler, K. M., and Lloyd, J. A. (2011) Transcription factors KLF1 and KLF2 positively regulate embryonic and fetal beta-globin genes through direct promoter binding, J. Biol. Chem., 286, 24819–24827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Im, H., Grass, J. A., Johnson, K. D., Kim, S. I., Boyer, M. E., Imbalzano, A. N., Bieker, J. J., and Bresnick, E. H. (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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhang, W., Kadam, S., Emerson, B. M., and Bieker, J. J. (2001) Site-specific acetylation by p300 or CREB binding protein regulates erythroid Kruppel-like factor transcriptional activity via its interaction with the SWI–SNF complex, Mol. Cell. Biol., 21, 2413–2422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Filipe, A., Li, Q., Deveaux, S., Godin, I., Romeo, P. H., Stamatoyannopoulos, G., and Mignotte, V. (1999) Regulation of embryonic/fetal globin genes by nuclear hormone receptors: a novel perspective on hemoglobin switching, EMBO J., 18, 687–697.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Avram, D., Fields, A., Pretty On Top, K., Nevrivy, D. J., Ishmael, J. E., and Leid, M. (2000) Isolation of a novel family of C(2)H(2) zinc finger proteins implicated in transcriptional repression mediated by chicken ovalbumin upstream promoter transcription factor (COUP-TF) orphan nuclear receptors, J. Biol. Chem., 275, 10315–10322.

    Article  CAS  PubMed  Google Scholar 

  61. Tanabe, O., Katsuoka, F., Campbell, A. D., Song, W., Yamamoto, M., Tanimoto, K., and Engel, J. D. (2002) An embryonic/fetal beta-type globin gene repressor contains a nuclear receptor TR2/TR4 heterodimer, EMBO J., 21, 3434–3442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Tanabe, O., Shen, Y., Liu, Q., Campbell, A. D., Kuroha, T., Yamamoto, M., and Engel, J. D. (2007) The TR2 and TR4 orphan nuclear receptors repress Gata1 transcription, Genes Dev., 21, 2832–2844.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Tanabe, O., McPhee, D., Kobayashi, S., Shen, Y., Brandt, W., Jiang, X., Campbell, A. D., Chen, Y. T., Chang, C., Yamamoto, M., Tanimoto, K., and Engel, J. D. (2007) Embryonic and fetal beta-globin gene repression by the orphan nuclear receptors, TR2 and TR4, EMBO J., 26, 2295–2306.

    Article  CAS  PubMed  Google Scholar 

  64. Choi, O. R., and Engel, J. D. (1988) Developmental regulation of beta-globin gene switching, Cell, 55, 17–26.

    Article  CAS  PubMed  Google Scholar 

  65. Zhou, W., Zhao, Q., Sutton, R., Cumming, H., Wang, X., Cerruti, L., Hall, M., Wu, R., Cunningham, J. M., and Jane, S. M. (2004) The role of p22 NF-E4 in human globin gene switching, J. Biol. Chem., 279, 26227–26232.

    Article  CAS  PubMed  Google Scholar 

  66. Verdel, A., Vavasseur, A., Le Gorrec, M., and Touat-Todeschini, L. (2009) Common themes in siRNA-mediated epigenetic silencing pathways, Int. J. Dev. Biol., 53, 245–257.

    Article  CAS  PubMed  Google Scholar 

  67. Allis, C. D., and Jenuwein, T. (2016) The molecular hall-marks of epigenetic control, Nat. Rev. Genet., 17, 487–500.

    Article  CAS  PubMed  Google Scholar 

  68. Hendrich, B., and Bird, A. (1998) Identification and characterization of a family of mammalian methyl-CpG binding proteins, Mol. Cell. Biol., 18, 6538–6547.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Khavari, D. A., Sen, G. L., and Rinn, J. L. (2010) DNA methylation and epigenetic control of cellular differentiation, Cell. Cycle, 9, 3880–3883.

    Article  CAS  PubMed  Google Scholar 

  70. Mabaera, R., Richardson, C. A., Johnson, K., Hsu, M., Fiering, S., and Lowrey, C. H. (2007) Developmental-and differentiation-specific patterns of human gamma-and beta-globin promoter DNA methylation, Blood, 110, 1343–1352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ng, H. H., Zhang, Y., Hendrich, B., Johnson, C. A., Turner, B. M., Erdjument-Bromage, H., Tempst, P., Reinberg, D., and Bird, A. (1999) MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex, Nat. Genet., 23, 58–61.

    Article  CAS  PubMed  Google Scholar 

  72. Feng, Q., and Zhang, Y. (2001) The MeCP1 complex represses transcription through preferential binding, remodeling, and deacetylating methylated nucleosomes, Genes Dev., 15, 827–832.

    CAS  PubMed  Google Scholar 

  73. Olivieri, N. F., Saunthararajah, Y., Thayalasuthan, V., Kwiatkowski, J., Ware, R. E., Kuypers, F. A., Kim, H. Y., Trachtenberg, F. L., and Vichinsky, E. P. (2011) A pilot study of subcutaneous decitabine in beta-thalassemia intermedia, Blood, 118, 2708–2711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Verdin, E., and Ott, M. (2015) 50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond, Nat. Rev. Mol. Cell Biol., 16, 258–264.

    Article  CAS  PubMed  Google Scholar 

  75. Hebbes, T. R., Clayton, A. L., Thorne, A. W., and Crane-Robinson, C. (1994) Core histone hyperacetylation co-maps with generalized DNase I sensitivity in the chicken beta-globin chromosomal domain, EMBO J., 13, 1823–1830.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Forsberg, E. C., Downs, K. M., Christensen, H. M., Im, H., Nuzzi, P. A., and Bresnick, E. H. (2000) Developmentally dynamic histone acetylation pattern of a tissue-specific chromatin domain, Proc. Natl. Acad. Sci. USA, 97, 14494–14499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Fu, X. H., Liu, D. P., and Liang, C. C. (2002) Chromatin structure and transcriptional regulation of the beta-globin locus, Exp. Cell Res., 278, 1–11.

    Article  CAS  PubMed  Google Scholar 

  78. Bulger, M., Schubeler, D., Bender, M. A., Hamilton, J., Farrell, C. M., Hardison, R. C., and Groudine, M. (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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Litt, M. D., Simpson, M., Recillas-Targa, F., Prioleau, M. N., and Felsenfeld, G. (2001) Transitions in histone acetylation reveal boundaries of three separately regulated neigh-boring loci, EMBO J., 20, 2224–2235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Ley, T. J., DeSimone, J., Anagnou, N. P., Keller, G. H., Humphries, R. K., Turner, P. H., Young, N. S., Keller, P., and Nienhuis, A. W. (1982) 5-Azacytidine selectively increases gamma-globin synthesis in a patient with beta+ thalassemia, N. Engl. J. Med., 307, 1469–1475.

    Article  CAS  PubMed  Google Scholar 

  81. Migliaccio, A. R., Rotili, D., Nebbioso, A., Atweh, G., and Mai, A. (2008) Histone deacetylase inhibitors and hemo-globin F induction in beta-thalassemia, Int. J. Biochem. Cell Biol., 40, 2341–2347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Boosalis, M. S., Bandyopadhyay, R., Bresnick, E. H., Pace, B. S., Van DeMark, K., Zhang, B., Faller, D. V., and Perrine, S. P. (2001) Short-chain fatty acid derivatives stimulate cell proliferation and induce STAT-5 activation, Blood, 97, 3259–3267.

    Article  CAS  PubMed  Google Scholar 

  83. Sangerman, J., Lee, M. S., Yao, X., Oteng, E., Hsiao, C. H., Li, W., Zein, S., Ofori-Acquah, S. F., and Pace, B. S. (2006) Mechanism for fetal hemoglobin induction by histone deacetylase inhibitors involves gamma-globin activation by CREB1 and ATF-2, Blood, 108, 3590–3599.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Jenuwein, T., and Allis, C. D. (2001) Translating the histone code, Science, 293, 1074–1080.

    Article  CAS  PubMed  Google Scholar 

  85. Litt, M. D., Simpson, M., Gaszner, M., Allis, C. D., and Felsenfeld, G. (2001) Correlation between histone lysine methylation and developmental changes at the chicken beta-globin locus, Science, 293, 2453–2455.

    Article  CAS  PubMed  Google Scholar 

  86. Hosey, A. M., Chaturvedi, C. P., and Brand, M. (2010) Crosstalk between histone modifications maintains the developmental pattern of gene expression on a tissue-specific locus, Epigenetics, 5, 273–281.

    Article  CAS  PubMed  Google Scholar 

  87. Brand, M., Ranish, J. A., Kummer, N. T., Hamilton, J., Igarashi, K., Francastel, C., Chi, T. H., Crabtree, G. R., Aebersold, R., and Groudine, M. (2004) Dynamic changes in transcription factor complexes during erythroid differentiation revealed by quantitative proteomics, Nat. Struct. Mol. Biol., 11, 73–80.

    Article  CAS  PubMed  Google Scholar 

  88. Renneville, A., Van Galen, P., Canver, M. C., McConkey, M., Krill-Burger, J. M., Dorfman, D. M., Holson, E. B., Bernstein, B. E., Orkin, S. H., Bauer, D. E., and Ebert, B. L. (2015) EHMT1 and EHMT2 inhibition induces fetal hemoglobin expression, Blood, 126, 1930–1939.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Chaturvedi, C. P., Hosey, A. M., Palii, C., Perez-Iratxeta, C., Nakatani, Y., Ranish, J. A., Dilworth, F. J., and Brand, M. (2009) Dual role for the methyltransferase G9a in the maintenance of beta-globin gene transcription in adult erythroid cells, Proc. Natl. Acad. Sci. USA, 106, 18303–18308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Vaissiere, T., Sawan, C., and Herceg, Z. (2008) Epigenetic interplay between histone modifications and DNA methylation in gene silencing, Mutat. Res., 659, 40–48.

    Article  CAS  PubMed  Google Scholar 

  91. Zhao, Q., Rank, G., Tan, Y. T., Li, H., Moritz, R. L., Simpson, R. J., Cerruti, L., Curtis, D. J., Patel, D. J., Allis, C. D., Cunningham, J. M., and Jane, S. M. (2009) PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing, Nat. Struct. Mol. Biol., 16, 304–311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Li, X., Hu, X., Patel, B., Zhou, Z., Liang, S., Ybarra, R., Qiu, Y., Felsenfeld, G., Bungert, J., and Huang, S. (2010) H4R3 methylation facilitates beta-globin transcription by regulating histone acetyltransferase binding and H3 acetylation, Blood, 115, 2028–2037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Miccio, A., Wang, Y., Hong, W., Gregory, G. D., Wang, H., Yu, X., Choi, J. K., Shelat, S., Tong, W., Poncz, M., and Blobel, G. A. (2010) NuRD mediates activating and repressive functions of GATA-1 and FOG-1 during blood development, EMBO J., 29, 442–456.

    Article  CAS  PubMed  Google Scholar 

  94. Hong, W., Nakazawa, M., Chen, Y. Y., Kori, R., Vakoc, C. R., Rakowski, C., and Blobel, G. A. (2005) FOG-1 recruits the NuRD repressor complex to mediate transcriptional repression by GATA-1, EMBO J., 24, 2367–2378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Cui, S., Kolodziej, K. E., Obara, N., Amaral-Psarris, A., Demmers, J., Shi, L., Engel, J. D., Grosveld, F., Strouboulis, J., and Tanabe, O. (2011) Nuclear receptors TR2 and TR4 recruit multiple epigenetic transcriptional corepressors that associate specifically with the embryonic beta-type globin promoters in differentiated adult erythroid cells, Mol. Cell. Biol., 31, 3298–3311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Bottardi, S., Mavoungou, L., and Milot, E. (2015) IKAROS: a multifunctional regulator of the polymerase II transcription cycle, Trends Genet., 31, 500–508.

    Article  CAS  PubMed  Google Scholar 

  97. O’Neill, D., Yang, J., Erdjument-Bromage, H., Bornschlegel, K., Tempst, P., and Bank, A. (1999) Tissue-specific and developmental stage-specific DNA binding by a mammalian SWI/SNF complex associated with human fetal-to-adult globin gene switching, Proc. Natl. Acad. Sci. USA, 96, 349–354.

    Article  PubMed  PubMed Central  Google Scholar 

  98. O’Neill, D. W., Schoetz, S. S., Lopez, R. A., Castle, M., Rabinowitz, L., Shor, E., Krawchuk, D., Goll, M. G., Renz, M., Seelig, H. P., Han, S., Seong, R. H., Park, S. D., Agalioti, T., Munshi, N., Thanos, D., Erdjument-Bromage, H., Tempst, P., and Bank, A. (2000) An IKAROS-containing chromatin-remodeling complex in adult-type erythroid cells, Mol. Cell. Biol., 20, 7572–7582.

    Article  PubMed  PubMed Central  Google Scholar 

  99. O’Neill, D., Bornschlegel, K., Flamm, M., Castle, M., and Bank, A. (1991) A DNA-binding factor in adult hematopoietic cells interacts with a pyrimidine-rich domain upstream from the human delta-globin gene, Proc. Natl. Acad. Sci. USA, 88, 8953–8957.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Dekker, J., Rippe, K., Dekker, M., and Kleckner, N. (2002) Capturing chromosome conformation, Science, 295, 1306–1311.

    Article  CAS  PubMed  Google Scholar 

  101. Tolhuis, B., Palstra, R. J., Splinter, E., Grosveld, F., and de Laat, W. (2002) Looping and interaction between hypersensitive sites in the active beta-globin locus, Mol. Cell, 10, 1453–1465.

    Article  CAS  PubMed  Google Scholar 

  102. Palstra, R. J., Tolhuis, B., Splinter, E., Nijmeijer, R., Grosveld, F., and de Laat, W. (2003) The beta-globin nuclear compartment in development and erythroid differentiation, Nat. Genet., 35, 190–194.

    Article  CAS  PubMed  Google Scholar 

  103. Ulianov, S. V., Galitsyna, A. A., Flyamer, I. M., Golov, A. K., Khrameeva, E. E., Imakaev, M. V., Abdennur, N. A., Gelfand, M. S., Gavrilov, A. A., and Razin, S. V. (2017) Activation of the alpha-globin gene expression correlates with dramatic upregulation of nearby non-globin genes and changes in local and large-scale chromatin spatial structure, Epigenetics Chromatin, 10, 35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Morgan, S. L., Mariano, N. C., Bermudez, A., Arruda, N. L., Wu, F., Luo, Y., Shankar, G., Jia, L., Chen, H., Hu, J. F., Hoffman, A. R., Huang, C. C., Pitteri, S. J., and Wang, K. C. (2017) Manipulation of nuclear architecture through CRISPR-mediated chromosomal looping, Nat. Commun., 8, 15993.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Drissen, R., Palstra, R. J., Gillemans, N., Splinter, E., Grosveld, F., Philipsen, S., and de Laat, W. (2004) The active spatial organization of the beta-globin locus requires the transcription factor EKLF, Genes Dev., 18, 2485–2490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Vakoc, C. R., Letting, D. L., Gheldof, N., Sawado, T., Bender, M. A., Groudine, M., Weiss, M. J., Dekker, J., and Blobel, G. A. (2005) Proximity among distant regulatory elements at the beta-globin locus requires GATA-1 and FOG-1, Mol. Cell, 17, 453–462.

    Article  CAS  PubMed  Google Scholar 

  107. Yun, W. J., Kim, Y. W., Kang, Y., Lee, J., Dean, A., and Kim, A. (2014) The hematopoietic regulator TAL1 is required for chromatin looping between the beta-globin LCR and human gamma-globin genes to activate transcription, Nucleic Acids Res., 42, 4283–4293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Van der Vliet, P. C., and Verrijzer, C. P. (1993) Bending of DNA by transcription factors, BioEssays, 15, 25–32.

    Article  PubMed  Google Scholar 

  109. Song, S. H., Hou, C., and Dean, A. (2007) A positive role for NLI/Ldb1 in long-range beta-globin locus control region function, Mol. Cell, 28, 810–822.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kiefer, C. M., Lee, J., Hou, C., Dale, R. K., Lee, Y. T., Meier, E. R., Miller, J. L., and Dean, A. (2011) Distinct Ldb1/NLI complexes orchestrate gamma-globin repression and reactivation through ETO2 in human adult erythroid cells, Blood, 118, 6200–6208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Krivega, I., and Dean, A. (2017) LDB1-mediated enhancer looping can be established independent of mediator and cohesin, Nucleic Acids Res., 45, 8255–8268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Huang, P., Keller, C. A., Giardine, B., Grevet, J. D., Davies, J. O. J., Hughes, J. R., Kurita, R., Nakamura, Y., Hardison, R. C., and Blobel, G. A. (2017) Comparative analysis of three-dimensional chromosomal architecture identifies a novel fetal hemoglobin regulatory element, Genes Dev., 31, 1704–1713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Fard, A. D., Hosseini, S. A., Shahjahani, M., Salari, F., and Jaseb, K. (2013) Evaluation of novel fetal hemoglobin inducer drugs in treatment of beta-hemoglobinopathy disorders, Int. J. Hematol. Oncol. Stem Cell Res., 7, 47–54.

    PubMed  PubMed Central  Google Scholar 

  114. Ansari, S., and Szallasi, A. (2012) Blood management by transfusion triggers: when less is more, Blood Transf., 10, 28–33.

    Google Scholar 

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Authors and Affiliations

  1. Institute of Gene Biology, Russian Academy of Sciences, 119334, Moscow, Russia

    O. V. Iarovaia, A. P. Kovina, N. V. Petrova, S. V. Razin, E. S. Ioudinkova & S. V. Ulianov

  2. French–Russian Laboratory for Research in Oncology LIA1066, Russia, France

    O. V. Iarovaia, A. P. Kovina, N. V. Petrova, S. V. Razin, E. S. Ioudinkova, Y. S. Vassetzky & S. V. Ulianov

  3. Lomonosov Moscow State University, Biological Faculty, 119991, Moscow, Russia

    A. P. Kovina, S. V. Razin & S. V. Ulianov

  4. Institut Gustave Roussy, 39 rue Camille-Desmoulins, 94805, Villejuif, France

    Y. S. Vassetzky

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  1. O. V. Iarovaia
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  2. A. P. Kovina
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  7. S. V. Ulianov
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Original Russian Text © O. V. Iarovaia, A. P. Kovina, N. V. Petrova, S. V. Razin, E. S. Ioudinkova, Y. S. Vassetzky, S. V. Ulianov, 2018, published in Biokhimiya, 2018, Vol. 83, No. 4, pp. 528–542.

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Iarovaia, O.V., Kovina, A.P., Petrova, N.V. et al. Genetic and Epigenetic Mechanisms of β-Globin Gene Switching. Biochemistry Moscow 83, 381–392 (2018). https://doi.org/10.1134/S0006297918040090

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