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Editorials
An early start of Coup-TFII promotes γ-globin gene expression in adult erythroid cells Stefania Bottardi1 and Eric Milot1,2
1Maisonneuve Rosemont Hospital Research Center, CIUSSS Est de l’Île de Montréal, Montréal, and 2Department of Medicine, University of Montreal, Montréal, Québec, Canada
E-mail: ERIC MILOT - e.milot.1@umontreal.ca doi:10.3324/haematol.2020.266791
Mutations of the human β-globin gene can affect the quantity or quality of the β-globin subunit and result in β-thalassemia or sickle cell anemia (respectively). These disorders can be regrouped under the designation of β-hemoglobinopathies and are the most frequent monogenic inherited diseases worldwide.1 The severity of β-hemoglobinopathies is strongly related to the nature of the mutation. Allogeneic hematopoietic stem cell transplantation is the most established cure for severe forms of β-hemoglobinopathies. However, like other clinical approaches, including gene therapy, which are used to correct this group of genetic diseases, allo- geneic hematopoietic stem cell transplantation is not without risk and can be associated with complications.2
vate γ-globin genes in adult erythroid cells.9 Another example of the complex regulation of globin genes is the number of transcription factors and complexes involved in γ-globin gene repression in adult erythroid cells. Indeed, although BCL11A is instrumental in the repression of γ- globin genes at an adult stage of development,10,11 the mutation of many different transcription factors and cofactors results in the partial reactivation of γ-globin genes.6 Thus, even if discoveries such as the dominant effect of BCL11A on γ-globin gene repression are promis- ing for the development of novel therapies to fight β- hemoglobinopathies, the main objective of different stud- ies remains the identification of a transcriptional activator capable of reactivating the γ-globin genes in adult ery- throid cells. A specific activator of the human β-globin gene was identified in KLF1 (EKLF),12 but until now such a transcriptional factor or cofactor specifically involved in the γ-globin gene activation was lacking. Importantly, in this issue of Haematologica, Fugazza et al. report that Coup- TFII, which was originally considered to be a γ-globin gene repressor, is a specific transcriptional activator of e- and γ-globin genes.13
Fugazza et al. report that, when expressed in adult ery- throid cells of healthy donors or thalassemic patients car- rying the Sardinian β039 mutation (β039-Thal), Coup-TFII can reactivate γ-globin gene expression.13 Their identifica- tion of Coup-TFII as a specific activator of γ-globin genes that can enhance HbF production in adult red blood cells brings hope, and increases the therapeutic possibilities to fight β-hemoglobinopathies.
The Coup-TFII (NR2F2/ARP-1) orphan nuclear receptor was initially identified as a component of the e- and γ-glo- bin gene-regulating complex NF-E3. It was proposed to be a positive regulator of the e-globin gene but a negative reg- ulator of γ-globin genes.14 Further investigation indicated that NF-E3/Coup-TFII can interfere with the recruitment of different transcriptional regulators to e- and γ-globin promoters, and unveiled conflicting results that could imply its involvement in the transcriptional activation of γ-globin genes.15 However, detailed molecular analysis of the precise effect of Coup-TFII on globin gene regulation during development has been complicated by the fact that it binds different regulatory regions of the β-globin locus and because Coup-TFII knockout is lethal at the embryon- ic stage of mouse development.
To study the importance of the transcription factor Coup-TFII in the regulation of embryonic and fetal globin genes, Fugazza et al. used transgenic mice carrying the human β-globin locus, a β-K562 human cell line and human blood cells from healthy or β039-Thal donors.13 In mice, they found that Coup-TFII expression occurs at the same developmental stage as endogenous murine or trans- genic human embryonic/fetal globin genes and, like the
The developmental switching from γ- to β-globin gene expression occurs around birth and results in the forma- tion of the adult form of hemoglobin, which is primarily composed of β and α-globin chains (HbA, α2β2). HbA gradually replaces the fetal hemoglobin (HbF, α2γ2) and hence, the developmental globin switching represents the genetic basis of HbF decline, which will drop to less than 1% within a few months of birth (by 6 months of age).3 However, a condition known as hereditary persistence of fetal hemoglobin (HPFH) is characterized by the mainte- nance of HbF at levels as high as 10% to 40% of total hemoglobin in adult blood.4 This condition is asympto- matic and can compensate for β-globin gene mutations that otherwise promote β-hemoglobinopathies. Indeed, increased HbF levels in adult blood cells is beneficial to patients with mutations affecting the quantity or quality of the β-globin chains. Thus, a substantial number of stud- ies have been performed to determine how the reactiva- tion of γ-globin genes could be efficiently reproduced in adult blood cells. However, the complexity of gene regu- lation at this multigenic locus and the absence of a known specific activator of the γ-globin genes that would not simultaneously increase the expression of the β-globin gene have delayed this achievement.
To modulate the expression levels of human β-type glo- bin genes, the influence of multiple control elements and different mechanisms of gene regulation have to be con- sidered. Furthermore, tissue- and development-specific expression of β-type globin genes relies on a complex net- work of transcription factors, cofactors and regulatory complexes.5-7 For instance, in addition to binding gene reg- ulatory regions, different transcription factors favor long- range interactions between promoters and distal regulato- ry elements of the locus in order to induce high levels of globin gene expression.8 Nonetheless, while many differ- ent transcriptional activators can influence these long- range interactions in the β-globin locus, it has been demonstrated that one engineered transcriptional regula- tor can be sufficient to induce these structures and reacti-
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