International Journal of Molecular Medical Science, 2024, Vol.14, No.4, 203-215 http://medscipublisher.com/index.php/ijmms 204 therapies, as well as the challenges and future directions in this field. By synthesizing findings from multiple studies, this review provides a detailed overview of the role of epigenetics in SCA and emphasizes future research directions. The study delves into the intricate relationship between epigenetics and SCA, offering a nuanced understanding of how epigenetic mechanisms can be harnessed to improve the management and treatment of this debilitating disease. 2 Introduction to Epigenetics 2.1 Basic concepts of epigenetics Epigenetics refers to heritable changes in gene expression that do not involve alterations to the underlying DNA sequence. These changes are mediated by various mechanisms, including DNA methylation, histone modifications, and non-coding RNAs (Peschansky andWahlestedt, 2014; Wei et al., 2017; Binnie et al., 2020). DNA methylation typically involves the addition of a methyl group to the cytosine residues in DNA, which can suppress gene expression. Histone modifications, such as acetylation and methylation, alter the chromatin structure, thereby influencing gene accessibility and transcription (Wilson, 2008; Dawson and Kouzarides, 2012). Non-coding RNAs, including microRNAs and long non-coding RNAs, play crucial roles in regulating gene expression at the post-transcriptional level (Peschansky andWahlestedt, 2014; Wei et al., 2017). 2.2 Role of epigenetics in gene regulation Epigenetic mechanisms are central to the regulation of gene expression, impacting various biological processes from development to disease. For instance, during erythropoiesis, a series of β-globin genes are sequentially activated and deactivated, serving as a model for coordinated gene expression regulated by epigenetic complexes (Wang et al., 2020). The transcription factor NRF2, known for its role in oxidative stress response, also regulates genes involved in epigenetic modifications, such as histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) (Figure 1) (Silva-Llanes et al., 2023). These regulatory mechanisms ensure that genes are expressed in a context-dependent manner, allowing cells to respond to environmental stimuli and maintain homeostasis (Cheng et al., 2019; Silva-Llanes et al., 2023). Silva-Llanes et al. (2023) explored the regulatory role of the transcription factor NRF2 on the DNA methyltransferases DNMT1, DNMT3a, and DNMT3b. The study's findings revealed that the absence of NRF2 leads to a significant decrease in the mRNA and protein expression of Dnmt1 and Dnmt3b, indicating that NRF2 plays a critical role in maintaining the normal expression of these enzymes. Additionally, time-course experiments further elucidated the dynamic changes in gene expression regulated by NRF2. These findings suggest that NRF2 may be involved in the epigenetic regulation of gene expression by modulating DNA methylation patterns. 2.3 Epigenetics and human disease Epigenetic dysregulation is implicated in a wide range of human diseases, including cancer, autoimmune disorders, and inflammatory conditions (Wilson, 2008; Dawson and Kouzarides, 2012). In cancer, aberrant DNA methylation and histone modifications can lead to the misregulation of genes involved in cell growth and differentiation, contributing to tumorigenesis (Dawson and Kouzarides, 2012; Cheng et al., 2019). Epigenetic changes are also central to the pathogenesis of sepsis, where host-pathogen interactions result in modifications that favor pathogen survival and alter the host immune response(Binnie et al., 2020). Moreover, epigenetic mechanisms are crucial in the development and progression of sickle cell anemia, where targeting specific epigenetic enzymes could potentially reactivate fetal hemoglobin production, offering a therapeutic strategy (Wang et al., 2020). 3 Genetic and Molecular Basis of Sickle Cell Anemia 3.1 Molecular pathogenesis of SCA Sickle Cell Anemia (SCA) is primarily caused by a single point mutation in the β-globin gene (HBB:c.20A>T), leading to the production of hemoglobin S (HbS) instead of the normal hemoglobin A (HbA). Under hypoxic conditions, HbS undergoes polymerization, causing red blood cells to adopt a sickle shape, which is more rigid and fragile. This morphological change triggers a cascade of pathophysiological events, including inflammation, cell adhesion, oxidative stress, and vaso-occlusion (Silva and Faustino, 2023). The polymerization of HbS is
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