{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nHBG2, which encodes the G‐γ subunit of fetal hemoglobin (HbF), plays a central role in the developmental regulation of hemoglobin synthesis. During fetal life HBG2 is highly expressed, but its transcription becomes repressed later when the switch to adult hemoglobin occurs. Several studies have shown that regulatory elements in the HBG2 promoter—such as the –158 XmnI (C→T) polymorphism—are key determinants of HbF expression. These genetic variants, together with interactions of transcription factors (for example, GATA‐1) and repressor complexes (including BCL11A and NuRD), modulate the silencing or persistence of HBG2 expression, thereby influencing the clinical severity of hemoglobinopathies such as sickle cell disease and β‐thalassemia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn-depth molecular analyses have revealed that point mutations or naturally occurring polymorphisms in the HBG2 promoter can disrupt transcription factor binding sites—such as mutations that abolish a GATA‐1 motif—or modify chromatin interactions. These disruptions can lead to a failure in the normal repression machinery, resulting in hereditary persistence of fetal hemoglobin (HPFH) or the production of hemoglobin variants with altered oxygen affinity. Functional studies employing techniques such as CRISPR-Cas9 genome editing have demonstrated that deliberate modification of these regulatory sites in HBG2 can reactivate its expression; this underscores the gene’s value as a therapeutic target for ameliorating the clinical manifestations of β-hemoglobinopathies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPopulation-based investigations across diverse ethnic groups have further refined our understanding of HBG2’s function. Numerous studies have correlated the presence and frequency of HBG2 promoter polymorphisms—including the XmnI site and several novel point mutations—with elevated HbF levels in patients with sickle cell disease, β-thalassemia intermedia, and other related conditions. These investigations indicate that HBG2-related genetic variations account for a significant proportion of the interindividual variability in HbF production and influence disease severity. Moreover, additional work has identified new HBG2 mutations that not only modify HbF expression but also result in structurally altered hemoglobin molecules, thereby impacting oxygen transport. Collectively, these findings highlight HBG2’s dual role as both a developmental gene and a modifier of hemoglobinopathy phenotypes, inspiring innovative therapeutic strategies to reactivate fetal hemoglobin expression in adult patients."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Guillaume Lettre, Vijay G Sankaran, Marcos André C Bezerra, et al. 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