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embryonic/fetal globin genes, Coup-TFII expression extin- guishes at embryonic day 12.5. However, they showed that only a small percentage of erythroid cells are charac- terized by the simultaneous expression of Coup-TFII and mouse or human embryonic/fetal globin genes. Their results indicate that Coup-TFII expression is initiated in the erythroid-myeloid precursor cells and precedes γ-glo- bin gene transcription during erythroid cell maturation, thus suggesting that the effect of Coup-TFII precedes the transcriptional activation of e- and γ-globin genes during erythroid cell differentiation/formation. Interestingly, in hematopoietic progenitor cells the human β-like globin genes are ‘primed’ for their subsequent transcriptional activation in erythroid cells.16-18 A few transcription factors have been reported to favor globin gene priming.19,20 Thus, Coup-TFII might also be involved in globin gene priming and, thereby, promote the specific activation of e- and γ- globin genes.
The effect of Coup-TFII expression was also tested in adult erythroid progenitor cells obtained from healthy donors and β039-Thal patients. As in the transgenic mouse model carrying the human β-globin locus, Coup-TFII expression was sufficient to reactivate the γ-globin genes in human adult erythroid cells. Furthermore, as indicated by the fold change in gene transcription, the effect of Coup-TFII was specific for γ- but not β-globin gene expression. Therefore, the results presented by Fugazza et al. indicate that the induction of Coup-TFII expression in adult erythroid cells could be beneficial for the treatment of patients with β-hemoglobinopathies.
To further characterize the molecular aspects linked to Coup-TFII-related activation of γ-globin genes, Coup-TFII knockout or overexpression was engineered in a human model cell line, β-K562 cells. Genome-wide analysis of Coup-TFII chromatin binding performed by chromatin immunoprecipitation (ChIP)-sequencing suggested that Coup-TFII is frequently recruited to genes/loci associated with hematologic diseases. This analysis identified signif- icant peaks of Coup-TFII binding within the β-globin locus control region hypersensitive sites 2 (HS2), HS3, HS4, and the γ−d intergenic region. Accordingly, it was found that Coup-TFII overexpression increases the long- range interaction between the locus control region and this γ−d intergenic region. Overall the analyses performed in β-K562 cells indicate that Coup-TFII binds to regulatory regions and influences the organization of the human β- globin locus. Furthermore, the ChIP-sequencing analysis and the finding that Coup-TFII peaks frequently overlap with GATA consensus binding sequences, led the authors to propose the participation of Coup-TFII in the erythro- poietic program.
Considered collectively, the results presented by Fugazza et al. elucidate the role of Coup-TFII in the regu- lation of e- and γ-globin genes during development.13 Unlike previously reported findings, these results reveal that Coup-TFII favors the transcriptional activation of γ- globin genes. Furthermore, they indicate that, when expressed in adult erythroid progenitor cells, Coup-TFII preferentially reactivate the expression of γ- over β-globin genes, thus providing new possibilities for the induction of γ-globin gene expression in adult erythroid cells.
Disclosures
No conflicts of interest to disclose.
Contributions
SB and EM wrote the manuscript.
Funding
This work was supported by a grant from the Canadian Institute of Health Research (CIHR: MOP133420) to EM.
References
1. Weatherall DJ. Phenotype-genotype relationships in monogenic dis- ease: lessons from the thalassaemias. Nat Rev Genet. 2001;2(4):245- 255.
2. Payen E, Leboulch P. Advances in stem cell transplantation and gene therapy in the beta-hemoglobinopathies. Hematology Am Soc Hematol Educ Program. 2012;2012:276-283.
3.Stamatoyannopoulos G. Control of globin gene expression during development and erythroid differentiation. Exp Hematol. 2005;33(3):259-271.
4. Menzel S, Thein SL. Genetic architecture of hemoglobin F control. Curr Opin Hematol. 2009;16(3):179-186.
5.Johnson KD, Grass JA, Boyer ME, et al. Cooperative activities of hematopoietic regulators recruit RNA polymerase II to a tissue-spe- cific chromatin domain. Proc Natl Acad Sci U S A. 2002;99(18): 11760-11765.
6. Andrieu-Soler C, Soler E. When basic science reaches into rational therapeutic design: from historical to novel leads for the treatment of beta-globinopathies. Curr Opin Hematol. 2020;27(3):141-148.
7. Rodriguez P, Bonte E, Krijgsveld J, et al. GATA-1 forms distinct acti- vating and repressive complexes in erythroid cells. EMBO J. 2005;24(13):2354-2366.
8. Noordermeer D, de Laat W. Joining the loops: beta-globin gene reg- ulation. IUBMB Life. 2008;60(12):824-833.
9. Deng W, Rupon JW, Krivega I, et al. Reactivation of developmentally silenced globin genes by forced chromatin looping. Cell. 2014;158(4):849-860.
10. Liu N, Hargreaves VV, Zhu Q, et al. Direct promoter repression by BCL11A controls the fetal to adult hemoglobin switch. Cell. 2018;173(2):430-442.e17.
11. Sankaran VG, Orkin SH. The switch from fetal to adult hemoglobin. Cold Spring Harb Perspect Med. 2013;3(1):a011643.
12. Siatecka M, Bieker JJ. The multifunctional role of EKLF/KLF1 during erythropoiesis. Blood. 2011;118(8):2044-2054.
13. Fugazza C, Barbarani G, Elangovan S, et al. The Coup-TFII orphan nuclear receptor is an activator of the gamma-globin gene. Haematologica. 2021;106(2):474-482.
14.Ronchi AE, Bottardi S, Mazzucchelli C, Ottolenghi S, Santoro C. Differential binding of the NFE3 and CP1/NFY transcription factors to the human gamma- and epsilon-globin CCAAT boxes. J Biol Chem. 1995;270(37):21934-21941.
15.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.
16. Papayannopoulou T, Brice M, Stamatoyannopoulos G. Hemoglobin F synthesis in vitro: evidence for control at the level of primitive ery- throid stem cells. Proc Natl Acad Sci U S A. 1977;74(7):2923-2927.
17. Papayannopoulou TH, Brice M, Stamatoyannopoulos G. Stimulation of fetal hemoglobin synthesis in bone marrow cultures from adult individuals. Proc Natl Acad Sci U S A. 1976;73(6):2033-2037.
18.Bottardi S, Aumont A, Grosveld F, Milot E. Developmental stage- specific epigenetic control of human beta-globin gene expression is potentiated in hematopoietic progenitor cells prior to their transcrip- tional activation. Blood. 2003;102(12):3989-3997.
19. Bottardi S, Ross J, Pierre-Charles N, Blank V, Milot E. Lineage-specif- ic activators affect beta-globin locus chromatin in multipotent hematopoietic progenitors. EMBO J. 2006;25(15):3586-3595.
20.Dulmovits BM, Appiah-Kubi AO, Papoin J, et al. Pomalidomide reverses gamma-globin silencing through the transcriptional repro- gramming of adult hematopoietic progenitors. Blood. 2016;127(11): 1481-1492.
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