Induction of human fetal hemoglobin expression by adenosine-2’,3’-dialdehyde

Journal of Translational Medicine

Quan Zhao³  Stephen M Jane²  Renxiang Tan³  Chi Ma³  Loretta Cerruti²  Fiona Brown²  Zhen Xu³  Ronghua Liu³  Junyi Ju³  Miaomiao Zhang³  Gerhard Rank²  Yinghong He¹ 

[1] School of Basic Medicine, Dali University, Yunnan, 671000, China;Department of Medicine, Monash University Central Clinical School, Alfred Hospital, Prahran, VIC, 3181, Australia;Molecular Immunology and Cancer Research Center, The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China

关键词: DNA methylation;    Histone arginine methylation;    Fetal globin;    Adenosine-2’,3’-dialdehyde (Adox);   

Others  :  828213
DOI  :  10.1186/1479-5876-11-14

 received in 2012-08-09, accepted in 2013-01-09,  发布年份 2013

【 摘 要 】

Background

Pharmacologic reactivation of fetal hemoglobin expression is a promising strategy for treatment of sickle cell disease and β-thalassemia. The objective of this study was to investigate the effect of the methyl transferase inhibitor adenosine-2’,3’-dialdehyde (Adox) on induction of human fetal hemoglobin (HbF) in K562 cells and human hematopoietic progenitor cells.

Methods

Expression levels of human fetal hemoglobin were assessed by northern blot analysis and Real-time PCR. HbF and adult hemoglobin (HbA) content were analyzed using high-performance liquid chromatography (HPLC). DNA methylation levels on human gamma-globin gene promoters were determined using Bisulfite sequence analysis. Enrichment of histone marks on genes was assessed by chromosome immunoprecipitation (ChIP).

Results

Adox induced γ-globin gene expression in both K562 cells and in human bone marrow erythroid progenitor cells through a mechanism potentially involving inhibition of protein arginine methyltransferase 5 (PRMT5).

Conclusions

The ability of methyl transferase inhibitors such as Adox to efficiently reactivate fetal hemoglobin expression suggests that these agents may provide a means of reactivating fetal globin expression as a therapeutic option for treating sickle cell disease and β-thalassemia.

【 授权许可】

   
2013 He et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Stamatoyannopoulos G: Control of globin gene expression during development and erythroid differentiation. Exp Hematol 2005, 33:259-271.
• [2]Perrine SP: Fetal globin stimulant therapies in the beta-hemoglobinopathies: principles and current potential. Pediatr Ann 2008, 37:339-346.
• [3]DeSimone J, Koshy M, Dorn L, Lavelle D, Bressler L, Molokie R, Talischy N: Maintenance of elevated fetal hemoglobin levels by decitabine during dose interval treatment of sickle cell anemia. Blood 2002, 99:3905-3908.
• [4]Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, Bonds DR: Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 1995, 332:1317-1322.
• [5]Pace BS, White GL, Dover GJ, Boosalis MS, Faller DV, Perrine SP: Short-chain fatty acid derivatives induce fetal globin expression and erythropoiesis in vivo. Blood 2002, 100:4640-4648.
• [6]Cao H, Stamatoyannopoulos G, Jung M: Induction of human gamma globin gene expression by histone deacetylase inhibitors. Blood 2004, 103:701-709.
• [7]Zhao Q, Rank G, Tan YT, Li H, Moritz RL, Simpson RJ, Cerruti L, Curtis DJ, Patel DJ, Allis CD, et al.: PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing. Nat Struct Mol Biol 2009, 16:304-311.
• [8]Rank G, Cerruti L, Simpson RJ, Moritz RL, Jane SM, Zhao Q: Identification of a PRMT5-dependent repressor complex linked to silencing of human fetal globin gene expression. Blood 2010, 116:1585-1592.
• [9]Kwak YT, Guo J, Prajapati S, Park KJ, Surabhi RM, Miller B, Gehrig P, Gaynor RB: Methylation of SPT5 regulates its interaction with RNA polymerase II and transcriptional elongation properties. Mol Cell 2003, 11:1055-1066.
• [10]Bruns AF, Grothe C, Claus P: Fibroblast growth factor 2 (FGF-2) is a novel substrate for arginine methylation by PRMT5. Biol Chem 2009, 390:59-65.
• [11]Sankaran VG, Menne TF, Xu J, Akie TE, Lettre G, Van Handel B, Mikkola HK, Hirschhorn JN, Cantor AB, Orkin SH: Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science 2008, 322:1839-1842.
• [12]Zhao Q, Zhou W, Rank G, Sutton R, Wang X, Cumming H, Cerruti L, Cunningham JM, Jane SM: Repression of human gamma-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, 107:2138-2145.
• [13]Wyczechowska D, Fabianowska-Majewska K: The effects of cladribine and fludarabine on DNA methylation in K562 cells. Biochem Pharmacol 2003, 65:219-225.
• [14]Hou Z, Peng H, Ayyanathan K, Yan KP, Langer EM, Longmore GD, Rauscher FJ 3rd: 3rd: The LIM protein AJUBA recruits protein arginine methyltransferase 5 to mediate SNAIL-dependent transcriptional repression. Mol Cell Biol 2008, 28:3198-3207.
• [15]Hermes M, Osswald H, Kloor D: Role of S-adenosylhomocysteine hydrolase in adenosine-induced apoptosis in HepG2 cells. Exp Cell Res 2007, 313:264-283.
• [16]Hoffman JL: The rate of transmethylation in mouse liver as measured by trapping S-adenosylhomocysteine. Arch Biochem Biophys 1980, 205:132-135.
• [17]Marafante E, Vahter M: The effect of methyltransferase inhibition on the metabolism of [74As]arsenite in mice and rabbits. Chem Biol Interact 1984, 50:49-57.
• [18]Mabaera R, Greene MR, Richardson CA, Conine SJ, Kozul CD, Lowrey CH: Neither DNA hypomethylation nor changes in the kinetics of erythroid differentiation explain 5-azacytidine’s ability to induce human fetal hemoglobin. Blood 2008, 111:411-420.
• [19]Lavelle D, Vaitkus K, Hankewych M, Singh M, DeSimone J: Effect of 5-aza-2’-deoxycytidine (Dacogen) on covalent histone modifications of chromatin associated with the epsilon-, gamma-, and beta-globin promoters in Papio anubis. Exp Hematol 2006, 34:339-347.
• [20]Fathallah H, Weinberg RS, Galperin Y, Sutton M, Atweh GF: Role of epigenetic modifications in normal globin gene regulation and butyrate-mediated induction of fetal hemoglobin. Blood 2007, 110:3391-3397.
• [21]Rupon JW, Wang SZ, Gaensler K, Lloyd J, Ginder GD: Methyl binding domain protein 2 mediates gamma-globin gene silencing in adult human betaYAC transgenic mice. Proc Natl Acad Sci USA 2006, 103:6617-6622.
• [22]Chin J, Singh M, Banzon V, Vaitkus K, Ibanez V, Kouznetsova T, Mahmud N, DeSimone J, Lavelle D: Transcriptional activation of the gamma-globin gene in baboons treated with decitabine and in cultured erythroid progenitor cells involves different mechanisms. Exp Hematol 2009, 37:1131-1142.
• [23]Bauer DE, Orkin SH: Update on fetal hemoglobin gene regulation in hemoglobinopathies. Curr Opin Pediatr 2011, 23:1-8.
• [24]Sankaran VG, Xu J, Ragoczy T, Ippolito GC, Walkley CR, Maika SD, Fujiwara Y, Ito M, Groudine M, Bender MA, et al.: Developmental and species-divergent globin switching are driven by BCL11A. Nature 2009, 460:1093-1097.
• [25]Zhou D, Liu K, Sun CW, Pawlik KM, Townes TM: KLF1 regulates BCL11A expression and gamma- to beta-globin gene switching. Nat Genet 2010, 42:742-744.
• [26]Ruthenburg AJ, Li H, Patel DJ, Allis CD: Multivalent engagement of chromatin modifications by linked binding modules. Nat Rev Mol Cell Biol 2007, 8:983-994.
• [27]Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K: High-resolution profiling of histone methylations in the human genome. Cell 2007, 129:823-837.