Epigenetic Regulation of β-Globin Genes and the Potential to Treat Hemoglobinopathies through Epigenome Editing

Abstract

Beta-like globin gene expression is developmentally regulated during life by transcription factors, chromatin looping and epigenome modifications of the β-globin locus. Epigenome modifications, such as histone methylation/demethylation and acetylation/deacetylation and DNA methylation, are associated with up- or down-regulation of gene expression. The understanding of these mechanisms and their outcome in gene expression has paved the way to the development of new therapeutic strategies for treating various diseases, such as β-hemoglobinopathies. Histone deacetylase and DNA methyl-transferase inhibitors are currently being tested in clinical trials for hemoglobinopathies patients. However, these approaches are often uncertain, non-specific and their global effect poses serious safety concerns. Epigenome editing is a recently developed and promising tool that consists of a DNA recognition domain (zinc finger, transcription activator-like effector or dead clustered regularly interspaced short palindromic repeats Cas9) fused to the catalytic domain of a chromatin-modifying enzyme. It offers a more specific targeting of disease-related genes (e.g., the ability to reactivate the fetal γ-globin genes and improve the hemoglobinopathy phenotype) and it facilitates the development of scarless gene therapy approaches. Here, we summarize the mechanisms of epigenome regulation of the β-globin locus, and we discuss the application of epigenome editing for the treatment of hemoglobinopathies.

Breaking genetic shackles: The advance of base editing in genetic disorder treatment

“…Elevating the levels of HbF within patients is one of the key strategies for the treatment or mitigation of these types of anemia. The γ-globin gene, encoded by the HBG gene and typically silenced in adulthood, is functional in fetal stages and can compensate for β-globin deficiency ( Fontana et al, 2023 ). The BCL11A gene plays a crucial role in repressing γ-globin gene expression in erythrocytes ( Bauer et al, 2013 ).…”

CRISPR-Based Gene Therapies: From Preclinical to Clinical Treatments

“…The system is more effective when transcriptional repressor domains (such as Krüppel-associated box, KRAB [33]) are fused to dCas9. Inversely, the CRISPRa system utilizes transcriptional activator domains (such as VP64, RTA, VP64, HSF1, and p65) to recruit RNA polymerase or TFs to promote and increase the expression of downstream genes [34,35]. Gene transcription can be altered at the epigenetic level by modulating DNA accessibility or chromatin structure at specific sites.…”

“…This approach is currently being used in a clinical trial for SCD (NCT05456880) (Table 1). Epigenetic activation of γ-globin has been proposed [35], both with zinc finger combined with transcriptional activator VP64 [61,62] and dCas9 fused with acetylase (p300) [37]; however, their γ-globin reactivation efficiency is lower compared with genome editing approaches.…”

In Silico Molecular Docking and Dynamics Simulation Analysis of Potential Histone Lysine Methyl Transferase Inhibitors for Managing β-Thalassemia

“…Furthermore, constant blood transfusion treatment might not be ideal for β-thalassemia-involved patients. Therefore, the search for the perfect alternative for managing abnormal erythropoiesis is of the utmost importance, and recently, much attention has been devoted to modulating the fetal hemoglobin (HBF) levels by inducing or reactivating the γ-globin expression through epigenetic regulators [9,10].…”