International Journal of Molecular Medical Science, 2024, Vol.14, No.4, 203-215 http://medscipublisher.com/index.php/ijmms 208 In sickle cell anemia, histone methylation patterns can influence the expression of genes involved in erythropoiesis and hemoglobin switching. For example, the methylation of histone H3 at lysine 27 (H3K27) has been implicated in the regulation of genes critical for red blood cell development and function (Carbajo-García et al., 2020). Alterations in histone methylation can thus impact the severity of sickle cell disease by affecting the expression of genes that modulate HbF levels and erythroid cell differentiation (Cheng et al., 2019; Neganova et al., 2020). 5.3 Therapeutic targeting of histone modifiers Targeting histone modifiers presents a promising therapeutic strategy for sickle cell anemia. The development of specific inhibitors for HATs, HDACs, HMTs, and HDMTs can potentially correct the aberrant gene expression profiles associated with the disease. For instance, HDAC inhibitors have shown promise in clinical trials for various cancers and are being investigated for their potential to induce HbF production in sickle cell patients (Kelly et al., 2010; Neganova et al., 2020; Rabal et al., 2021). Moreover, the design of multitarget epigenetic inhibitors that simultaneously modulate multiple histone modifications could offer a more comprehensive approach to treating sickle cell anemia. Such inhibitors could potentially enhance HbF production while also correcting other epigenetic abnormalities associated with the disease (Rabal et al., 2021). 6 DNA Methylation Patterns in Sickle Cell Anemia 6.1 Overview of DNA methylation DNA methylation is a crucial epigenetic modification involving the addition of a methyl group to the 5-carbon position of the cytosine ring, primarily at CpG dinucleotides in the mammalian genome. This modification plays a significant role in regulating gene expression by either recruiting proteins involved in gene repression or inhibiting the binding of transcription factors to DNA (Klose and Bird, 2006; Moore et al., 2013). The methylation patterns are dynamically regulated during development, leading to stable and unique methylation profiles in differentiated cells that control tissue-specific gene transcription (Moore et al., 2013; Smith and Meissner, 2013). Additionally, DNA methylation is essential for maintaining genome integrity and cellular homeostasis, with its dysregulation linked to various diseases, including cancer (Breiling and Lyko, 2015; Alagia and Gullerová, 2022). 6.2 Aberrant methylation in SCA In the context of Sickle Cell Anemia (SCA), aberrant DNA methylation patterns have been observed, which may contribute to the pathophysiology of the disease. Studies have shown that the methylation status of specific genomic regions can influence the expression of genes involved in hemoglobin production and erythropoiesis. For instance, differential methylation of CpG sites in the promoters of globin genes can affect their transcriptional activity, potentially exacerbating the clinical manifestations of SCA (Lister et al., 2009; Smith and Meissner, 2013). Moreover, the dynamic regulation of DNA methylation at gene distal regulatory elements, such as enhancers, suggests that methylation turnover might play a role in the rapid response to environmental stimuli and cellular stress, which are common in SCA patients (Parry et al., 2020). 6.3 DNA methylation as a therapeutic target Given the pivotal role of DNA methylation in gene regulation, targeting aberrant methylation patterns presents a promising therapeutic strategy for SCA. Epigenetic therapies, such as DNA methyltransferase inhibitors, could potentially restore normal methylation patterns and gene expression profiles in affected individuals (Klose and Bird, 2006; Alagia and Gullerová, 2022). Additionally, the development of high-throughput and single-molecule mapping techniques has enabled the detailed profiling of methylation patterns, facilitating the identification of specific epigenetic alterations in SCA (Gabrieli et al., 2021). These advancements could lead to the development of personalized epigenetic therapies aimed at correcting the underlying molecular defects in SCA patients. 7 Role of Non-Coding RNAs in Epigenetic Regulation 7.1 Introduction to non-coding RNAs Non-coding RNAs (ncRNAs) are a diverse class of RNA molecules that do not encode proteins but play crucial roles in regulating gene expression at various levels, including epigenetic regulation. These ncRNAs include
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