Comprehensive regulation of γ-globin expression by epigenetic modifications and protein post-translational modifications

Abstract

As a member of the hemoglobin family, γ-globin is usually persistently expressed at high levels to perform the oxygen-carrying function during fetal development. In recent years, related gene editing clinical trials have confirmed that reactivation of γ-globin expression is a promising therapeutic strategy for treating β-hemoglobinopathies, including β-thalassemia and sickle cell disease. Human γ-globin expression is finely regulated by multiple mechanisms, and a deeper understanding of the mechanisms will help develop drugs that target its activation. With the advancement of biotechnology, epigenetic modifications (EMs) and protein post-translational modifications (PPTMs) have shown irreplaceable roles in the regulation of γ-globin expression. Therefore, this review will comprehensively summarize the regulatory mechanisms of EMs and PPTMs on γ-globin to provide new ideas for the treatment of β-hemoglobinopathies.

Keywords: Epigenetic modifications; Protein post-translational modifications; Regulatory mechanisms; β-hemoglobinopathies; γ-globin.

Fig. 1

Schematic of EMs and PPTMs regulating γ-globin expression. EMs, epigenetic modifications; PPTMs, protein post-translational modifications.

Fig. 2

Production and main function of γ-globin. A Schematic of genomic location and protein structure of γ-globin. B Function of γ-globin in fetus, β-thal, and SCD. γ-globin can efficiently transport oxygen and reduce the aggregation and precipitation of abnormal hemoglobin, thereby minimizing damage to red blood cells and improving patients’ anemia of β-thal and SCD. SCD, sickle cell disease; β-thal, β-thalassemia; HbF, fetal hemoglobin.

Fig. 3

Histone modifications mediated the regulation of γ-globin expression. A Histone methylation-mediated suppression of γ-globin. PRMT5, FoP, WDR5, and LSD1 are the key participants in this process. B Histone acetylation-driven activation of γ-globin expression. γ-globin expression is modulated by a cohort of transcription factors and small molecules that act through histone acetylation. C p38 MAPK signaling pathway-mediated histone phosphoacetylation promotes γ-globin expression. PT, as a stimulating signal, activates the p38 MAPK signaling pathway and simultaneously cooperates with histone acetylation modification to jointly promote the expression of γ-globin. PRMT, Protein Arginine Methyltransferases; DNMT3A, DNA Methyltransferase 3A; EHMT1/2, Euchromatic Histone Lysine Methyltransferase 1 and 2 ; LSD1, Lysine-Specific Demethylase 1; WDR5, WD Repeat Domain 5; NURD, Nucleosome Remodeling and Deacetylase Complex; HDAC, Histone Deacetylase; KLF1, Krüppel-like Factor 1; BCL11A, B-cell Lymphoma/Leukemia 11A; SIRT1, Sirtuin 1; PRMT5, Protein Arginine Methyltransferase 5; ADOX, Adenosine Dialdehyde; PT, Plastrum testudinis.

Fig. 4

Mechanistic overview of non-coding RNA-mediated γ-globin expression regulation. miRNAs modulate γ-globin expression either by repressing translation or by targeting transcription factors. LncRNAs act cooperatively to regulate γ-globin expression. CircRNAs act as competitive miRNA sponges, thereby regulating the expression of γ-globin. GATA-1, GATA-binding factor 1; SP1, Specificity Protein 1; KLF3, Krüppel-like Factor 3; STAT3, Signal Transducer and Activator of Transcription 3; ERF, Ets-Related Factor; ELK, Ets Like-1 protein; SOX6, SRY-box 6.