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Expert Review of Hematology Volume 11, 2018 - Issue 1
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Review

The intrinsic genetic and epigenetic regulator factors as therapeutic targets, and the effect on fetal globin gene expression

Pegah AdelvandDepartment of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, IranView further author information
,
Mohammed HamidDepartment of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, IranCorrespondence[email protected]
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Soroush SardariDrug Design and Bioinformatics Unit, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, IranView further author information
Pages 71-81 | Received 10 Sep 2016, Accepted 15 Nov 2017, Published online: 04 Dec 2017

  • Schechter AN. Hemoglobin research and the origins of molecular medicine. Blood. 2008;112(10):3927–3938.
  • Wilber A, Nienhuis AW, Persons DA. Transcriptional regulation of fetal to adult hemoglobin switching: new therapeutic opportunities. Blood. 2011;117(15):3945–3953.
  • Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis. 2010;5:11.
  • Origa R. Beta-Thalassemia. 2000 Sep 28 [Updated 2015 May 14]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1426
  • Roseff SD. Sickle cell disease: a review. Immunohematology. 2009;25(2):67–74.
  • Constantinou K. Is blood transfusion therapy the ideal treatment for β-thalassemia intermedia? Open J Hematol. 2012;3:3–5.
  • Cavazzana-Calvo M, Payen E, Negre O, et al. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassemia. Nature. 2010;467(7313):318–322.
  • Arumugam P, Malik P. Genetic therapy for beta-thalassemia: from the bench to the bedside. Hematol Am Soc Hematol Educ Program. 2010;2010:445–450.
  • Musallam KM, Taher AT, Cappellini MD, et al. Clinical experience with fetal hemoglobin induction therapy in patients with β-thalassemia. Blood. 2013;121(12):2199–2212.
  • Peterson KR, Fedosyuk H, Harju-Baker S. LCR 5‘ hypersensitive site specificity for globin gene activation within the active chromatin hub. Nucleic Acids Res. 2012;40(22):11256–11269.
  • Li Q, Peterson KR, Fang X, et al. Locus control regions. Blood. 2002;100(9):3077–3086.
  • Harju-Baker S, Costa FC, Fedosyuk H, et al. Silencing of Aγ-globin gene expression during adult definitive erythropoiesis mediated by GATA-1-FOG-1-Mi2 complex binding at the −566 GATA site. Mol Cell Biol. 2008;28(10):3101–3113.
  • Cho Y, Song S-H, Lee JJ, et al. The role of transcriptional activator GATA-1 at human beta-globin HS2. Nucleic Acids Res. 2008;36(14):4521–4528.
  • Jane SM, Ney PA, Vanin EF, et al. Identification of a stage selector element in the human gamma-globin gene promoter that fosters preferential interaction with the 5ʹ HS2 enhancer when in competition with the beta-promoter. EMBO J. 1992;11(8):2961–2969.
  • Langdon SD, Kaufman RE. Gamma-globin gene promoter elements required for interaction with globin enhancers. Blood. 1998;91(1):309–318.
  • Xu J, Sankaran VG, Ni M, et al. Transcriptional silencing of {gamma}-globin by BCL11A involves long-range interactions and cooperation with SOX6. Genes Dev. 2010;24(8):783–798.
  • Brunmeir R, Lagger S, Seiser C. Histone deacetylase HDAC1/HDAC2-controlled embryonic development and cell differentiation. Int J Dev Biol. 2009;53(2–3):275–289.
  • Gnanapragasam MN, Scarsdale JN, Amaya ML, et al. p66α–MBD2 coiled-coil interaction and recruitment of Mi-2 are critical for globin gene silencing by the MBD2-NuRD complex. Proc Natl Acad Sci USA. 2011;108(18):7487–7492.
  • Amaya M, Desai M, Gnanapragasam MN, et al. Mi2β-mediated silencing of the fetal g-globin gene in adult erythroid cells. Blood. 2013;121(17):3493–3501.
  • Bank A. Regulation of human fetal hemoglobin: new players, new complexities. Blood. 2006;107(2):435–443.
  • Chakalova L, Osborne CS, Dai Y-F, et al. The Corfu deltabeta thalassemia deletion disrupts gamma-globin gene silencing and reveals post-transcriptional regulation of HbF expression. Blood. 2005;105(5):2154–2160.
  • He Y, Rank G, Zhang M, et al. Induction of human fetal hemoglobin expression by adenosine-2ʹ, 3ʹ-dialdehyde. J Transl Med. 2013;11:14.
  • Fraser P, Pruzina S, Antoniou M, et al. Each hypersensitive site of the human beta-globin locus control region confers a different developmental pattern of expression on the globin genes. Genes Dev. 1993;7(1):106–113.
  • Li Q, Harju S, Peterson KR. Locus control regions: coming of age at a decade plus. Trends Genet. 1999;15(10):403–408.
  • Catani L, Vianelli N, Amabile M, et al. Nuclear factor-erythroid 2 (NF-E2) expression in normal and malignant megakaryocytopoiesis. Leukemia. 2002;16(9):1773–1781.
  • Zhou D, Pawlik KM, Ren J, et al. Differential binding of erythroid Kruppel-like factor to embryonic/fetal globin gene promoters during development. J Biol Chem. 2006;281(23):16052–16057.
  • Woon Kim Y, Kim S, Geun Kim C, et al. The distinctive roles of erythroid specific activator GATA-1 and NF-E2 in transcription of the human fetal γ-globin genes. Nucleic Acids Res. 2011;39(16):6944–6955.
  • Navas PA, Li Q, Peterson KR, et al. Activation of the beta-like globin genes in transgenic mice is dependent on the presence of the beta-locus control region. Hum Mol Genet. 2002;11(8):893–903.
  • Guy LG, Kothary R, De Repentigny Y, et al. The beta-globin locus control region enhances transcription of but does not confer position-independent expression onto the lacZ gene in transgenic mice. Embo J. 1996;15(14):3713–3721.
  • Zhang SB, Qian RL. The interaction between the human beta-globin locus control region and nuclear matrix. Cell Res. 2002;12(5–6):411–416.
  • Navas PA, Peterson KR, Li Q, et al. 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. 1998;18(7):4188–4196.
  • Tewari R, Gillemans N, Wijgerde M, et al. Erythroid Krüppel-like factor (EKLF) is active in primitive and definitive erythroid cells and is required for the function of 5ʹHS3 of the beta-globin locus control region. Embo J. 1998;17(8):2334–2341.
  • Xu J, Bauer DE, Kerenyi MA, et al. Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A. Proc Natl Acad Sci USA. 2013;110(16):6518–6523.
  • Li Q, Stamatoyannopoulos G. Hypersensitive site 5 of the human beta locus control region functions as a chromatin insulator. Blood. 1994;84(5):1399–1401.
  • Gaszner M, Felsenfeld FG. Insulators: exploiting transcriptional and epigenetic mechanisms. Nat Rev Genet. 2006;7(9):703–713.
  • Omori A, Tanabe O, Engel JD, et al. Adult stage gamma-globin silencing is mediated by a promoter direct repeat element. Mol Cell Biol. 2005;25(9):3443–3451.
  • Tanabe O, Katsuoka F, Campbell AD, et al. An embryonic/fetal β-type globin gene repressor contains a nuclear receptor TR2/TR4 heterodimer. Embo J. 2002;21(13):3434–3442.
  • Liberati C, Cera MR, Secco P, et al. Cooperation and competition between the binding of COUP-TFII and NF-Y on human epsilon- and gamma-globin gene promoters. J Biol Chem. 2001;276(45):41700–41709.
  • Makala LH, Torres CM, Clay EL, et al. Fetal hemoglobin induction to treat β-hemoglobinopathies: from bench to bedside. J Hematol Transfus. 2014;2(2):1018.
  • Anagnou NP, Moulton AD, Keller G, et al. Cis-acting sequences that affect the expression of the human fetal gamma-globin genes. Prog Clin Biol Res. 1985;191:163–182.
  • Fang X, Han H, Stamatoyannopoulos G, et al. Developmentally specific role of the CCAAT box in regulation of human gamma-globin gene expression. J Biol Chem. 2004;279(7):5444–5449.
  • Thein SL, Menzel S, Lathrop M, et al. Control of fetal hemoglobin: new insights emerging from genomics and clinical implications. Hum Mol Genet. 2009;18(R2):R216–223.
  • Cardoso GL, Diniz IG, Silva AN, et al. DNA polymorphisms at BCL11A, HBS1L-MYB and Xmn1-HBG2 site loci associated with fetal hemoglobin levels in sickle cell anemia patients from Northern Brazil. Blood Cells Mol Dis. 2014;53(4):176–179.
  • Gilman JG, Huisman TH. DNA sequence variation associated with elevated fetal G gamma globin production. Blood. 1985;66(4):783–787.
  • Dadheech S, Jain S, Madhulatha D, et al. Association of Xmn1-158 γG variant with severity and HbF levels in β-thalassemia major and sickle cell anaemia. Mol Biol Rep. 2014;41(5):3331–3337.
  • Stadhouders R, Aktuna S, Thongjuea S, et al. HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers. J Clin Invest. 2014;124(4):1699–1710.
  • Uda M, Galanello R, Sanna S, et al. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proc Natl Acad Sci USA. 2008;105(5):1620–1625.
  • Nguyen TK, Joly P, Bardel C, et al. The XmnI (G) gamma polymorphism influences hemoglobin F synthesis contrary to BCL11A and HBS1L-MYB SNPs in a cohort of 57 beta-thalassemia intermedia patients. Blood Cells Mol Dis. 2010;45(2):124–127.
  • Alhashem YN, Vinjamur DS, Basu M, et al. Transcription factors KLF1 and KLF2 positively regulate embryonic and fetal beta-globin genes through direct promoter binding. J Biol Chem. 2011;286(28):24819–24827.
  • Tallack MR, Perkins AC. Three fingers on the switch: Krüppel-like factor 1 regulation of γ-globin to β-globin gene switching. Curr Opin Hematol. 2013;20(3):193–200.
  • Bauer DE, Orkin SH. Update on fetal hemoglobin gene regulation in hemoglobinopathies. Curr Opin Pediatr. 2011;23(1):1–8.
  • Nitta T, Kawano F, Yamashiro Y, et al. A new Krüppel-like factor 1 mutation (c.947G > A or p.C316Y) in humans causes β-thalassemia minor. Hemoglobin. 2015;39(2):121–126.
  • Asano H, Li XS, Stamatoyannopoulos G. FKLF-2: a novel Krüppel-like transcriptional factor that activates globin and other erythroid lineage genes. Blood. 2000;95(11):3578–3584.
  • Kalra IS, Alam MM, Choudhary PK, et al. Krüppel-like Factor 4 activates HBG gene expression in primary erythroid cells. Br J Haematol. 2011;154(2):248–259.
  • Andrews NC. The NF-E2 transcription factor. Int J Biochem Cell Biol. 1998;30(4):429–432.
  • Sun T, Chen Y, Yulong H, et al. A stage-specific protein factor binding to a CACCC motif in both human β-globin gene promoter and 5ʹ-HS2 region. Cell Research. 1994;4:135–143.
  • Haga SB, Fu S, Karp JE, et al. BP1, a new homeobox gene, is frequently expressed in acute leukemias. Leukemia. 2000;14(11):1867–1875.
  • Mpollo MS, Beaudoin M, Berg PE, et al. BP1 is a negative modulator of definitive erythropoiesis. Nucleic Acids Res. 2006;34(18):5232–5237.
  • Zoueva OP, Garrett LJ, Bodine D, et al. BP1 motif in the human β-globin promoter affects β-globin expression during embryonic/fetal erythropoiesis in transgenic mice bearing the human β-globin gene. Blood Cells Mol Dis. 2008;41(3):244–251.
  • Zhou W, Clouston DR, Wang X, et al. Induction of human fetal globin gene expression by a novel erythroid factor, NF-E4. Mol Cell Biol. 2000;20(20):7662–7672.
  • Jane SM, Nienhuis AW, Cunningham JM. Hemoglobin switching in man and chicken is mediated by a heteromeric complex between the ubiquitous transcription factor CP2 and a developmentally specific protein. Embo J. 1995;14(1):97–105.
  • Jane SM, Gumucio DL, Ney PA, et al. Methylation-enhanced binding of Sp1 to the stage selector element of the human gamma-globin gene promoter may regulate development specificity of expression. Mol Cell Biol. 1993;13(6):3272–3281.
  • Peschle C, Gabbianelli M, Testa U, et al. c-kit ligand reactivates fetal hemoglobin synthesis in serum-free culture of stringently purified normal adult burst-forming unit-erythroid. Blood. 1993;81(2):328–336.
  • Gabbianelli M, Testa U, Massa A, et al. Hemoglobin switching in unicellular erythroid culture of sibling erythroid burst-forming units: kit ligand induces a dose-dependent fetal hemoglobin reactivation potentiated by sodium butyrate. Blood. 2000;95(11):3555–3561.
  • Yun WJ, Kim YW, Kang Y, et al. The hematopoietic regulator TAL1 is required for chromatin looping between the β-globin LCR and human γ-globin genes to activate transcription. Nucleic Acids Res. 2014;42(7):4283–4293.
  • Grieco AJ, Billett HH, Green NS, et al. Variation in gamma-globin expression before and after induction with hydroxyurea associated with BCL11A, KLF1 and TAL1. PLoS One. 2015;10(6):e0129431.
  • Homo sapiens gene NFE4, encoding transcription factor NF-E4. NCBI: Gene Summary; 2010. Available from: http://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=human&l=NFE4
  • Gallarda JL, Foley KP, Yang ZY, et al. The beta-globin stage selector element factor is erythroid-specific promoter/enhancer binding protein NF-E4. Genes Dev. 1989;3(12A):1845–1859.
  • Zhou W, Zhao Q, Sutton R, et al. The role of p22 NF-E4 in human globin gene switching. J Biol Chem. 2004;279(25):26227–26232.
  • Zhao Q, Zhou W, Rank G, et al. Repression of human γ-globin gene expression by a short isoform of the NF-E4 protein is associated with loss of NF-E2 and RNA polymerase II recruitment to the promoter. Blood. 2006;107(5):2138–2145.
  • Yang Z, Engel JD. Biochemical characterization of the developmental stage- and tissue-specific erythroid transcription factor, NF-E4. J Biol Chem. 1994;269:10079–10087.
  • Menzel S, Garner C, Gut I, et al. A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15. Nat Genet. 2007;39(10):1197–1199.
  • Michelson AM. Developmental biology. From genetic association to genetic switch. Science. 2008;322(5909):1803–1804.
  • Sankaran VG, Menne TF, Xu J, et al. Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science. 2008;322(5909):1839–1842.
  • Xu J, Peng C, Sankaran VG, et al. Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing. Science. 2011;334(6058):993–996.
  • Ferreira R, Ohneda K, Yamamoto M, et al. GATA1 function, a paradigm for transcription factors in hematopoiesis. Mol Cell Biol. 2005;25(4):1215–1227.
  • Dore LC, Amigo JD, Dos Santos CO, et al. A GATA-1-regulated microRNA locus essential for erythropoiesis. Proc Natl Acad Sci USA. 2008;105(9):3333–3338.
  • Le Guezennec X, Vermeulen M, Brinkman AB, et al. MBD2/NuRD and MBD3/NuRD, two distinct complexes with different biochemical and functional properties. Mol Cell Biol. 2006;26(3):843–851.
  • Johnson KD, Boyer ME, Kang J-A, et al. Friend of GATA-1-independent transcriptional repression: a novel mode of GATA-1 function. Blood. 2007;109(12):5230–5233.
  • Cantor AB, Katz SG, Orkin SH. Distinct domains of the GATA-1 cofactor FOG-1 differentially influence erythroid versus megakaryocytic maturation. Mol Cell Biol. 2002;22(12):4268–4279.
  • Bank A, O’Neill D, Lopez R, et al. Role of intergenic human gamma-delta-globin sequences in human hemoglobin switching and reactivation of fetal hemoglobin in adult erythroid cells. Ann N Y Acad Sci. 2005;1054:48–54.
  • Ginder GD. Epigenetic regulation of fetal globin gene expression in adult erythroid cells. Transl Res. 2015;165(1):115–125.
  • Witt O, Monkemeyer S, Rönndahl G, et al. Induction of fetal hemoglobin expression by the histone deacetylase inhibitor apicidin. Blood. 2003;101(5):2001–2007.
  • Bauer DE, Kamran SC, Orkin SH. Reawakening fetal hemoglobin: prospects for new therapies for the β-globin disorders. Blood. 2012;120(15):2945–2953.
  • Mabaera R, Richardson CA, Johnson K, et al. Developmental- and differentiation-specific patterns of human gamma- and beta-globin promoter DNA methylation. Blood. 2007;110(4):1343–1352.
  • Perrine SP. Fetal globin induction–can it cure beta thalassemia? Hematol Am Soc Hematol Educ Program. 2005;2005(1):38–44.
  • Atweh GF, DeSimone J, Saunthararajah Y, et al. Hemoglobinopathies. Hematol Am Soc Hematol Educ Program. 2003;2003(1):14–39. doi: 10.1182/asheducation-2003.1.14. Available from: http://asheducationbook.hematologylibrary.org/content/2003/1/14.long
  • Fard AD, Hosseini SA, Shahjahani M, et al. Evaluation of novel fetal hemoglobin inducer drugs in treatment of β-hemoglobinopathy disorders. Int J Hematol Oncol Stem Cell Res. 2013;7(3):47–54.
  • Olivieri NF, Weatherall DJ. The therapeutic reactivation of fetal haemoglobin. Hum Mol Genet. 1998;7(10):1655–1658.
  • Zimmerman SA, Schultz WH, Davis JS, et al. Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease. Blood. 2004;103(6):2039–2045.
  • Lowrey CH, Nienhuis AW. Brief report: treatment with azacitidine of patients with end-stage beta-thalassemia. N Engl J Med. 1993;329(12):845–848.
  • Marianna P, Kollia P, Akel S, et al. Valproic acid, trichostatin and their combination with hemin preferentially enhance gamma-globin gene expression in human erythroid liquid cultures. Haematologica. 2001;86(7):700–705.
  • Hamid M, Mahjoubi F, Akbari MT, et al. Molecular analysis of gamma-globin promoters, HS-111 and 3ʹHS1, in beta-thalassemia intermedia patients associated with high levels of Hb F. Hemoglobin. 2009;33(6):428–438.
  • Hamid M, Mahjoubi F, Akbari MT, et al. Transient expression assay of Agamma-588 (A/G) mutations in the K562 cell line. Iran Biomed J. 2011;15(1–2):15–21.
  • Hashemi-Gorji F, Hamid M, Arab A, et al. Relationship between DNA polymorphisms at the BCL11A and HBS1L-MYB loci in β-thalassemia patients with increased fetal hemoglobin levels. Sci J Blood Transfus Organ. 2011;8(3):149–157.
  • Breda L, Motta I, Lourenco S, et al. Forced chromatin looping raises fetal hemoglobin in adult sickle cells to higher levels than pharmacologic inducers. Blood. 2016;128(8):1139–1143.

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