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Omics Studies in Hemoglobinopathies

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Abstract

Hemoglobinopathies include all genetic diseases of hemoglobin and are grouped into thalassemia syndromes and structural hemoglobin variants. The β-thalassemias constitute a group of severe anemias with monogenic inheritance, caused by β-globin gene mutations. This review is focused on omics studies in hemoglobinopathies and mainly β-thalassemia, and discusses genomic, epigenomic, transcriptomic, proteomic and metabolomic findings. Omics analyses have identified various disease modifiers with an impact on disease severity and efficacy of treatments. These modifiers have contributed to the understanding of globin genes regulation/hemoglobin switching and the development of novel therapies. How omics data and their integration can contribute to efficient patient stratification, therapeutic management, improvements in existing treatments and application of novel personalized therapies is discussed.

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References

  1. Williams TN, Weatherall DJ. World distribution, population genetics, and health burden of the hemoglobinopathies. Cold Spring Harb Perspect Med. 2012;2(9):a011692.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Muncie HL Jr, Campbell J. Alpha and beta thalassemia. Am Fam Physician. 2009;80(4):339–44.

    PubMed  Google Scholar 

  3. Cao A, Galanello R. Beta-thalassemia. Genet Med. 2010;12(2):61–76.

    Article  CAS  PubMed  Google Scholar 

  4. Rivella S. Ineffective erythropoiesis and thalassemias. Curr Opin Hematol. 2009;16(3):187–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Moher D, Stewart L, Shekelle P. Implementing PRISMA-P: recommendations for prospective authors. Syst Rev. 2016;28(5):15.

    Article  Google Scholar 

  6. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015;2(350):g7647.

    Article  Google Scholar 

  7. Thein SL, Menzel S. Discovering the genetics underlying foetal haemoglobin production in adults. Br J Haematol. 2009;145(4):455–67.

    Article  CAS  PubMed  Google Scholar 

  8. Galanello R, Cao A. Relationship between genotype and phenotype. Thalassemia intermedia. Ann N Y Acad Sci. 1998;850:325–33.

    Article  CAS  PubMed  Google Scholar 

  9. Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis. 2010;21(5):11.

    Article  Google Scholar 

  10. Razak SAA, Murad NAA, Masra F, Chong DLS, Abdullah N, Jalil N, et al. Genetic Modifiers of fetal haemoglobin (HbF) and phenotypic severity in beta-thalassemia patients. Curr Mol Med. 2018;18(5):295–305.

    Article  CAS  PubMed  Google Scholar 

  11. Galanello R, Perseu L, Melis MA, Cipollina L, Barella S, Giagu N, et al. Hyperbilirubinaemia in heterozygous beta-thalassaemia is related to co-inherited Gilbert’s syndrome. Br J Haematol. 1997;99(2):433–6.

    Article  CAS  PubMed  Google Scholar 

  12. Origa R, Galanello R, Perseu L, Tavazzi D, Domenica Cappellini M, Terenzani L, et al. Cholelithiasis in thalassemia major. Eur J Haematol. 2009;82(1):22–5.

    Article  CAS  PubMed  Google Scholar 

  13. Economou-Petersen E, Aessopos A, Kladi A, Flevari P, Karabatsos F, Fragodimitri C, et al. Apolipoprotein E epsilon4 allele as a genetic risk factor for left ventricular failure in homozygous beta-thalassemia. Blood. 1998;92(9):3455–9.

    CAS  PubMed  Google Scholar 

  14. Kremastinos DT, Flevari P, Spyropoulou M, Vrettou H, Tsiapras D, Stavropoulos-Giokas CG. Association of heart failure in homozygous beta-thalassemia with the major histocompatibility complex. Circulation. 1999;100(20):2074–8.

    Article  CAS  PubMed  Google Scholar 

  15. Origa R, Satta S, Matta G, Galanello R. Glutathione S-transferase gene polymorphism and cardiac iron overload in thalassaemia major. Br J Haematol. 2008;142(1):143–5.

    Article  CAS  PubMed  Google Scholar 

  16. Longo F, Zecchina G, Sbaiz L, Fischer R, Piga A, Camaschella C. The influence of hemochromatosis mutations on iron overload of thalassemia major. Haematologica. 1999;84(9):799–803.

    CAS  PubMed  Google Scholar 

  17. Perrotta S, Cappellini MD, Bertoldo F, Servedio V, Iolascon G, D’Agruma L, et al. Osteoporosis in beta-thalassaemia major patients: analysis of the genetic background. Br J Haematol. 2000;111(2):461–6.

    Article  CAS  PubMed  Google Scholar 

  18. Dresner Pollack R, Rachmilewitz E, Blumenfeld A, Idelson M, Goldfarb AW. Bone mineral metabolism in adults with beta-thalassaemia major and intermedia. Br J Haematol. 2000;111(3):902–7.

    CAS  PubMed  Google Scholar 

  19. Sollaino MC, Paglietti ME, Perseu L, Giagu N, Loi D, Galanello R. Association of alpha globin gene quadruplication and heterozygous beta thalassemia in patients with thalassemia intermedia. Haematologica. 2009;94(10):1445–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Thein SL, Wainscoat JS, Sampietro M, Old JM, Cappellini D, Fiorelli G, et al. Association of thalassaemia intermedia with a beta-globin gene haplotype. Br J Haematol. 1987;65(3):367–73.

    Article  CAS  PubMed  Google Scholar 

  21. Gilman JG, Huisman TH. DNA sequence variation associated with elevated fetal G gamma globin production. Blood. 1985;66(4):783–7.

    CAS  PubMed  Google Scholar 

  22. Yavarian M, Karimi M, Bakker E, Harteveld CL, Giordano PC. Response to hydroxyurea treatment in Iranian transfusion-dependent beta-thalassemia patients. Haematologica. 2004;89(10):1172–8.

    CAS  PubMed  Google Scholar 

  23. Karimi M, Haghpanah S, Farhadi A, Yavarian M. Genotype-phenotype relationship of patients with beta-thalassemia taking hydroxyurea: a 13-year experience in Iran. Int J Hematol. 2012;95(1):51–6.

    Article  CAS  PubMed  Google Scholar 

  24. Italia KY, Jijina FF, Merchant R, Panjwani S, Nadkarni AH, Sawant PM, et al. Effect of hydroxyurea on the transfusion requirements in patients with severe HbE-beta-thalassaemia: a genotypic and phenotypic study. J Clin Pathol. 2010;63(2):147–50.

    Article  CAS  PubMed  Google Scholar 

  25. Dixit A, Chatterjee TC, Mishra P, Choudhry DR, Mahapatra M, Tyagi S, et al. Hydroxyurea in thalassemia intermedia—a promising therapy. Ann Hematol. 2005;84(7):441–6.

    Article  CAS  PubMed  Google Scholar 

  26. Labie D, Dunda-Belkhodja O, Rouabhi F, Pagnier J, Ragusa A, Nagel RL. The −158 site 5′ to the G gamma gene and G gamma expression. Blood. 1985;66(6):1463–5.

    CAS  PubMed  Google Scholar 

  27. Craig JE, Rochette J, Fisher CA, Weatherall DJ, Marc S, Lathrop GM, et al. Dissecting the loci controlling fetal haemoglobin production on chromosomes 11p and 6q by the regressive approach. Nat Genet. 1996;12(1):58–64.

    Article  CAS  PubMed  Google Scholar 

  28. Thein SL, Menzel S, Peng X, Best S, Jiang J, Close J, et al. Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus on chromosome 6q23 influencing fetal hemoglobin levels in adults. Proc Natl Acad Sci USA. 2007;104(27):11346–51.

    Article  CAS  PubMed  Google Scholar 

  29. Creary LE, Ulug P, Menzel S, McKenzie CA, Hanchard NA, Taylor V, et al. Genetic variation on chromosome 6 influences F cell levels in healthy individuals of African descent and HbF levels in sickle cell patients. PLoS One. 2009;4(1):e4218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Stadhouders R, Aktuna S, Thongjuea S, Aghajanirefah A, Pourfarzad F, van Ijcken W, et al. HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers. J Clin Investig. 2014;124(4):1699–710.

    Article  CAS  PubMed  Google Scholar 

  31. Smith EC, Orkin SH. Hemoglobin genetics: recent contributions of GWAS and gene editing. Hum Mol Genet. 2016;25(R2):R99–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Menzel S, Garner C, Gut I, Matsuda F, Yamaguchi M, Heath S, 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):1197–9.

    Article  CAS  PubMed  Google Scholar 

  33. Uda M, Galanello R, Sanna S, Lettre G, Sankaran VG, Chen W, 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):1620–5.

    Article  PubMed  Google Scholar 

  34. Borg J, Papadopoulos P, Georgitsi M, Gutierrez L, Grech G, Fanis P, et al. Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin. Nat Genet. 2010;42(9):801–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhou D, Liu K, Sun CW, Pawlik KM, Townes TM. KLF1 regulates BCL11A expression and gamma- to beta-globin gene switching. Nat Genet. 2010;42(9):742–4.

    Article  CAS  PubMed  Google Scholar 

  36. Gambari R. The role of OMICS research in understanding phenotype variation in thalassaemia: the THALAMOSS Project. In: 4th Pan-European conference on haemoglobinopathies and rare anaemias thalassemia reports; 2014. p. 81–5.

  37. Pule GD, Ngo Bitoungui VJ, Chetcha Chemegni B, Kengne AP, Antonarakis S, Wonkam A. Association between variants at BCL11A erythroid-specific enhancer and fetal hemoglobin levels among sickle cell disease patients in Cameroon: implications for future therapeutic interventions. Omics. 2015;19(10):627–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sebastiani P, Farrell JJ, Alsultan A, Wang S, Edward HL, Shappell H, et al. BCL11A enhancer haplotypes and fetal hemoglobin in sickle cell anemia. Blood Cells Mol Dis. 2015;54(3):224–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Maroofi N, Azarkeivan A, Banihashemi S, Mohammadparast S, Aghajanirefah A, Banan M. An enhancer haplotype may influence BCL11A expression levels and the response to hydroxyurea in beta-thalassemia patients. Pharmacogenomics. 2017;18(10):955–7.

    Article  CAS  Google Scholar 

  40. Liu N, Hargreaves VV, Zhu Q, Kurland JV, Hong J, Kim W, et al. Direct promoter repression by BCL11A controls the fetal to adult hemoglobin switch. Cell. 2018;173(2):430–442 e17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Funnell AP, Prontera P, Ottaviani V, Piccione M, Giambona A, Maggio A, et al. 2p15-p16.1 microdeletions encompassing and proximal to BCL11A are associated with elevated HbF in addition to neurologic impairment. Blood. 2015;126(1):89–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lettre G, Sankaran VG, Bezerra MA, Araujo AS, Uda M, Sanna S, et al. DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. Proc Natl Acad Sci USA. 2008;105(33):11869–74.

    Article  PubMed  Google Scholar 

  43. Farrell JJ, Sherva RM, Chen ZY, Luo HY, Chu BF, Ha SY, et al. A 3-bp deletion in the HBS1L-MYB intergenic region on chromosome 6q23 is associated with HbF expression. Blood. 2011;117(18):4935–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pule GD, Mowla S, Novitzky N, Wonkam A. Hydroxyurea down-regulates BCL11A, KLF-1 and MYB through miRNA-mediated actions to induce gamma-globin expression: implications for new therapeutic approaches of sickle cell disease. Clin Transl Med. 2016;5(1):15.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Garner CP, Tatu T, Best S, Creary L, Thein SL. Evidence of genetic interaction between the beta-globin complex and chromosome 8q in the expression of fetal hemoglobin. Am J Hum Genet. 2002;70(3):793–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Garner C, Silver N, Best S, Menzel S, Martin C, Spector TD, et al. Quantitative trait locus on chromosome 8q influences the switch from fetal to adult hemoglobin. Blood. 2004;104(7):2184–6.

    Article  CAS  PubMed  Google Scholar 

  47. Thein SL, Craig JE. Genetics of Hb F/F cell variance in adults and heterocellular hereditary persistence of fetal hemoglobin. Hemoglobin. 1998;22(5–6):401–14.

    Article  CAS  PubMed  Google Scholar 

  48. Borg J, Phylactides M, Bartsakoulia M, Tafrali C, Lederer C, Felice AE, et al. KLF10 gene expression is associated with high fetal hemoglobin levels and with response to hydroxyurea treatment in beta-hemoglobinopathy patients. Pharmacogenomics. 2012;13(13):1487–500.

    Article  CAS  PubMed  Google Scholar 

  49. Chen D, Zuo Y, Zhang X, Ye Y, Bao X, Huang H, et al. A genetic variant ameliorates beta-thalassemia severity by epigenetic-mediated elevation of human fetal hemoglobin expression. Am J Hum Genet. 2017;101(1):130–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Canver MC, Lessard S, Pinello L, Wu Y, Ilboudo Y, Stern EN, et al. Variant-aware saturating mutagenesis using multiple Cas9 nucleases identifies regulatory elements at trait-associated loci. Nat Genet. 2017;49(4):625–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Canver MC, Smith EC, Sher F, Pinello L, Sanjana NE, Shalem O, et al. BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis. Nature. 2015;527(7577):192–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bauer DE, Kamran SC, Lessard S, Xu J, Fujiwara Y, Lin C, et al. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science. 2013;342(6155):253–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Vierstra J, Reik A, Chang KH, Stehling-Sun S, Zhou Y, Hinkley SJ, et al. Functional footprinting of regulatory DNA. Nat Methods. 2015;12(10):927–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Neishabury M, Zamani F, Keyhani E, Azarkeivan A, Abedini SS, Eslami MS, et al. The influence of the BCL11A polymorphism on the phenotype of patients with beta thalassemia could be affected by the beta globin locus control region and/or the Xmn1-HBG2 genotypic background. Blood Cells Mol Dis. 2013;51(2):80–4.

    Article  CAS  PubMed  Google Scholar 

  55. Brendel C, Guda S, Renella R, Bauer DE, Canver MC, Kim YJ, et al. Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype. J Clin Investig. 2016;126(10):3868–78.

    Article  PubMed  Google Scholar 

  56. Psatha N, Reik A, Phelps S, Zhou Y, Dalas D, Yannaki E, et al. Disruption of the BCL11A erythroid enhancer reactivates fetal hemoglobin in erythroid cells of patients with beta-thalassemia major. Mol Ther Methods Clin Dev. 2018;21(10):313–26.

    Article  CAS  Google Scholar 

  57. Martyn GE, Wienert B, Yang L, Shah M, Norton LJ, Burdach J, et al. Natural regulatory mutations elevate the fetal globin gene via disruption of BCL11A or ZBTB7A binding. Nat Genet. 2018;50(4):498–503.

    Article  CAS  PubMed  Google Scholar 

  58. Grevet JD, Lan X, Hamagami N, Edwards CR, Sankaranarayanan L, Ji X, et al. Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells. Science. 2018;361(6399):285–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Schwarze K, Buchanan J, Taylor JC, Wordsworth S. Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature. Genet Med. 2018;20:1122–30.

    Article  PubMed  Google Scholar 

  60. Stranneheim H, Wedell A. Exome and genome sequencing: a revolution for the discovery and diagnosis of monogenic disorders. J Intern Med. 2016;279(1):3–15.

    Article  CAS  PubMed  Google Scholar 

  61. Steinberg-Shemer O, Ulirsch JC, Noy-Lotan S, Krasnov T, Attias D, Dgany O, et al. Whole-exome sequencing identifies an alpha-globin cluster triplication resulting in increased clinical severity of beta-thalassemia. Cold Spring Harb Mol Case Stud. 2017;3(6):a001941.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ginder GD. Epigenetic regulation of fetal globin gene expression in adult erythroid cells. Transl Res. 2015;165(1):115–25.

    Article  CAS  PubMed  Google Scholar 

  63. Costa D, Capuano M, Sommese L, Napoli C. Impact of epigenetic mechanisms on therapeutic approaches of hemoglobinopathies. Blood Cells Mol Dis. 2015;55(2):95–100.

    Article  CAS  PubMed  Google Scholar 

  64. Muralidhar SA, Ramakrishnan V, Kalra IS, Li W, Pace BS. Histone deacetylase 9 activates gamma-globin gene expression in primary erythroid cells. J Biol Chem. 2011;286(3):2343–53.

    Article  CAS  PubMed  Google Scholar 

  65. Shi L, Cui S, Engel JD, Tanabe O. Lysine-specific demethylase 1 is a therapeutic target for fetal hemoglobin induction. Nat Med. 2013;19(3):291–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Gao T, Nie Y, Guo J. Hypermethylation of the gene LARP2 for noninvasive prenatal diagnosis of beta-thalassemia based on DNA methylation profile. Mol Biol Rep. 2012;39(6):6591–8.

    Article  CAS  PubMed  Google Scholar 

  67. Chadwick LH, The NIH. Roadmap Epigenomics Program data resource. Epigenomics. 2012;4(3):317–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Replogle JM, De Jager PL. Epigenomics in translational research. Transl Res. 2015;165(1):7–11.

    Article  PubMed  Google Scholar 

  69. Breda L, Casu C, Gardenghi S, Bianchi N, Cartegni L, Narla M, et al. Therapeutic hemoglobin levels after gene transfer in beta-thalassemia mice and in hematopoietic cells of beta-thalassemia and sickle cells disease patients. PLoS One. 2012;7(3):e32345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Cosenza LC, Breda L, Breveglieri G, Zuccato C, Finotti A, Lampronti I, et al. A validated cellular biobank for beta-thalassemia. J Transl Med. 2016;2(14):255.

    Article  CAS  Google Scholar 

  71. Stephanou C, Papasavva P, Zachariou M, Patsali P, Epitropou M, Ladas P, et al. Suitability of small diagnostic peripheral-blood samples for cell-therapy studies. Cytotherapy. 2017;19(2):311–26.

    Article  CAS  PubMed  Google Scholar 

  72. Leecharoenkiat A, Wannatung T, Lithanatudom P, Svasti S, Fucharoen S, Chokchaichamnankit D, et al. Increased oxidative metabolism is associated with erythroid precursor expansion in beta0-thalassaemia/Hb E disease. Blood Cells Mol Dis. 2011;47(3):143–57.

    Article  CAS  PubMed  Google Scholar 

  73. Ponnikorn S, Panichakul T, Sresanga K, Wongborisuth C, Roytrakul S, Hongeng S, et al. Phosphoproteomic analysis of apoptotic hematopoietic stem cells from hemoglobin E/beta-thalassemia. J Transl Med. 2011;25(9):96.

    Article  CAS  Google Scholar 

  74. Xu J, Bauer DE, Kerenyi MA, Vo TD, Hou S, Hsu YJ, et al. Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A. Proc Natl Acad Sci USA. 2013;110(16):6518–23.

    Article  PubMed  Google Scholar 

  75. Shi L, Lin YH, Sierant MC, Zhu F, Cui S, Guan Y, et al. Developmental transcriptome analysis of human erythropoiesis. Hum Mol Genet. 2014;23(17):4528–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Roselli EA, Mezzadra R, Frittoli MC, Maruggi G, Biral E, Mavilio F, et al. Correction of beta-thalassemia major by gene transfer in haematopoietic progenitors of pediatric patients. EMBO Mol Med. 2010;2(8):315–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Pourfarzad F, von Lindern M, Azarkeivan A, Hou J, Kia SK, Esteghamat F, et al. Hydroxyurea responsiveness in beta-thalassemic patients is determined by the stress response adaptation of erythroid progenitors and their differentiation propensity. Haematologica. 2013;98(5):696–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Chondrou V, Kolovos P, Sgourou A, Kourakli A, Pavlidaki A, Kastrinou V, et al. Whole transcriptome analysis of human erythropoietic cells during ontogenesis suggests a role of VEGFA gene as modulator of fetal hemoglobin and pharmacogenomic biomarker of treatment response to hydroxyurea in beta-type hemoglobinopathy patients. Hum Genomics. 2017;11(1):24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Masuda T, Wang X, Maeda M, Canver MC, Sher F, Funnell AP, et al. Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin. Science. 2016;351(6270):285–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kurita R, Suda N, Sudo K, Miharada K, Hiroyama T, Miyoshi H, et al. Establishment of immortalized human erythroid progenitor cell lines able to produce enucleated red blood cells. PLoS One. 2013;8(3):e59890.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Buenrostro JD, Giresi PG, Zaba LC, Chang HY, Greenleaf WJ. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat Methods. 2013;10(12):1213–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Renneville A, Van Galen P, Canver MC, McConkey M, Krill-Burger JM, Dorfman DM, et al. EHMT1 and EHMT2 inhibition induces fetal hemoglobin expression. Blood. 2015;126(16):1930–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004;5(7):522–31.

    Article  CAS  PubMed  Google Scholar 

  84. Bianchi N, Zuccato C, Finotti A, Lampronti I, Borgatti M, Gambari R. Involvement of miRNA in erythroid differentiation. Epigenomics. 2012;4(1):51–65.

    Article  CAS  PubMed  Google Scholar 

  85. Bianchi N, Finotti A, Ferracin M, Lampronti I, Zuccato C, Breveglieri G, et al. Increase of microRNA-210, decrease of raptor gene expression and alteration of mammalian target of rapamycin regulated proteins following mithramycin treatment of human erythroid cells. PLoS One. 2015;10(4):e0121567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Bianchi N, Zuccato C, Lampronti I, Borgatti M, Gambari R. Expression of miR-210 during erythroid differentiation and induction of gamma-globin gene expression. BMB Rep. 2009;42(8):493–9.

    Article  CAS  PubMed  Google Scholar 

  87. Ma Y, Wang B, Jiang F, Wang D, Liu H, Yan Y, et al. A feedback loop consisting of microRNA 23a/27a and the beta-like globin suppressors KLF3 and SP1 regulates globin gene expression. Mol Cell Biol. 2013;33(20):3994–4007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Finotti A, Breda L, Lederer CW, Bianchi N, Zuccato C, Kleanthous M, et al. Recent trends in the gene therapy of beta-thalassemia. J Blood Med. 2015;6:69–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Lulli V, Romania P, Morsilli O, Cianciulli P, Gabbianelli M, Testa U, et al. MicroRNA-486-3p regulates gamma-globin expression in human erythroid cells by directly modulating BCL11A. PLoS One. 2013;8(4):e60436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lee YT, de Vasconcellos JF, Yuan J, Byrnes C, Noh SJ, Meier ER, et al. LIN28B-mediated expression of fetal hemoglobin and production of fetal-like erythrocytes from adult human erythroblasts ex vivo. Blood. 2013;122(6):1034–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Fornari TA, Lanaro C, Albuquerque DM, Ferreira R, Costa FF. Featured Article: Modulation of fetal hemoglobin in hereditary persistence of fetal hemoglobin deletion type-2, compared to Sicilian deltabeta-thalassemia, by BCL11A and SOX6-targeting microRNAs. Exp Biol Med (Maywood). 2017;242(3):267–74.

    Article  CAS  Google Scholar 

  92. Lai K, Jia S, Yu S, Luo J, He Y. Genome-wide analysis of aberrantly expressed lncRNAs and miRNAs with associated co-expression and ceRNA networks in beta-thalassemia and hereditary persistence of fetal hemoglobin. Oncotarget. 2017;8(30):49931–43.

    PubMed  PubMed Central  Google Scholar 

  93. Vallelian F, Gelderman-Fuhrmann MP, Schaer CA, Puglia M, Opitz L, Baek JH, et al. Integrative proteome and transcriptome analysis of extramedullary erythropoiesis and its reversal by transferrin treatment in a mouse model of beta-thalassemia. J Proteome Res. 2015;14(2):1089–100.

    Article  CAS  PubMed  Google Scholar 

  94. Musharraf SG, Iqbal A, Ansari SH, Parveen S, Khan IA, Siddiqui AJ. Beta-thalassemia patients revealed a significant change of untargeted metabolites in comparison to healthy individuals. Sci Rep. 2017;13(7):42249.

    Article  CAS  Google Scholar 

  95. Papassotiriou I, Panetsos F, Livadara T, Dimopoulou M, Tzivaras A, Voskaridou E. Targeted metabolomic profiles are strongly correlated with metabolic alterations in patients with sickle cell/beta thalassemia disease. Blood. 2013;2013:4675.

    Google Scholar 

  96. Iqbal A, Ansari SH, Parveen S, Khan IA, Siddiqui AJ, Musharraf SG. Hydroxyurea treated β-thalassemia children demonstrate a shift in metabolism towards healthy pattern. Sci Rep. 2018;8(1):15152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kumar Sarker S, Islam MT, Sarower Bhuyan G, Sultana N, Begum MN, Al Mahmud-Un-Nabi M, et al. Impaired acylcarnitine profile in transfusion-dependent beta-thalassemia major patients in Bangladesh. J Adv Res. 2018;12:55–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Lohani N, Bhargava N, Munshi A, Ramalingam S. Pharmacological and molecular approaches for the treatment of beta-hemoglobin disorders. J Cell Physiol. 2018;233(6):4563–77.

    Article  CAS  PubMed  Google Scholar 

  99. Canver MC, Orkin SH. Customizing the genome as therapy for the beta-hemoglobinopathies. Blood. 2016;127(21):2536–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Dever DP, Porteus MH. The changing landscape of gene editing in hematopoietic stem cells: a step towards Cas9 clinical translation. Curr Opin Hematol. 2017;24(6):481–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Cavazzana M, Antoniani C, Miccio A. Gene therapy for beta-hemoglobinopathies. Mol Ther. 2017;25(5):1142–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Orkin SH. Recent advances in globin research using genome-wide association studies and gene editing. Ann N Y Acad Sci. 2016;1368(1):5–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Esrick EB, Bauer DE. Genetic therapies for sickle cell disease. Semin Hematol. 2018;55(2):76–86.

    Article  PubMed  Google Scholar 

  104. Bauer DE, Kamran SC, Orkin SH. Reawakening fetal hemoglobin: prospects for new therapies for the beta-globin disorders. Blood. 2012;120(15):2945–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Polo JM, Dell’Oso T, Ranuncolo SM, Cerchietti L, Beck D, Da Silva GF, et al. Specific peptide interference reveals BCL6 transcriptional and oncogenic mechanisms in B-cell lymphoma cells. Nat Med. 2004;10(12):1329–35.

    Article  CAS  PubMed  Google Scholar 

  106. Ghetu AF, Corcoran CM, Cerchietti L, Bardwell VJ, Melnick A, Prive GG. Structure of a BCOR corepressor peptide in complex with the BCL6 BTB domain dimer. Mol Cell. 2008;29(3):384–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Cerchietti LC, Ghetu AF, Zhu X, Da Silva GF, Zhong S, Matthews M, et al. A small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo. Cancer Cell. 2010;17(4):400–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Bauer DE, Orkin SH. Update on fetal hemoglobin gene regulation in hemoglobinopathies. Curr Opin Pediatr. 2011;23(1):1–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Karczewski KJ, Snyder MP. Integrative omics for health and disease. Nat Rev Genet. 2018;19(5):299–310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Bouhaddani SE, Uh HW, Jongbloed G, Hayward C, Klaric L, Kielbasa SM, et al. Integrating omics datasets with the OmicsPLS package. BMC Bioinform. 2018;19(1):371.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Basic Research Center, Biomedical Research Foundation, Academy of Athens, Soranou tou Ephessiou 4, 115 27, Athens, Greece

    Eleni Katsantoni

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  1. Eleni Katsantoni
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Correspondence to Eleni Katsantoni.

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ΕΚ was supported by EU FP7 THALAMOSS Project number 306201.

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EK has no conflicts to report, declares no competing financial interests, and apologizes to those whose work was not cited due to space limitations.

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Katsantoni, E. Omics Studies in Hemoglobinopathies. Mol Diagn Ther 23, 223–234 (2019). https://doi.org/10.1007/s40291-019-00386-1

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