International Journal of Molecular Medical Science, 2024, Vol.14 http://medscipublisher.com/index.php/ijmms © 2024 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved.
International Journal of Molecular Medical Science, 2024, Vol.14 http://medscipublisher.com/index.php/ijmms © 2024 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. MedSci Publisher, operated by Sophia Publishing Group (SPG), is an international Open Access publishing platform that publishes scientific journals in the field of life science. Sophia Publishing Group (SPG), founded in British Columbia of Canada, is a multilingual publisher. Publisher MedSci Publisher Editedby Editorial Team of International Journal of Molecular Medical Science Email: edit@ijmms.medscipublisher.com Website: http://medscipublisher.com/index.php/ijmms Address: 11388 Stevenston Hwy, PO Box 96016, Richmond, V7A 5J5, British Columbia Canada International Journal of Molecular Medical Science (ISSN 1927-6656) is an open access, peer reviewed journal published online by MedSci Publisher. The journal publishes scientific articles like original research articles, case reports, review articles, editorials, short communications and correspondence of the high quality pertinent to all aspects of human biology, pathophysiology and molecular medical science, including genomics, transcriptomics, proteomics, metabolomics of disease therapy, clinical pharmacology, clinical biochemistry, vaccines, immunology, microbiology, epidemiology, aging, cancer biology, infectious diseases, neurological diseases and myopathies, stem cells and regenerative medicine, vascular and cardiovascular biology, as well as the important implications for human health and clinical practice research. All the articles published in International Journal of Molecular Medical Science are Open Access, and are distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MedSci Publisher uses CrossCheck service to identify academic plagiarism through the world’s leading plagiarism prevention tool, iParadigms, and to protect the original authors’ copyrights.
International Journal of Molecular Medical Science (online), 2024, Vol. 14, No. 4 ISSN 1927-6656 http://medscipublisher.com/index.php/ijmms © 2024 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. Latest Content Epigenetic Regulatory Mechanisms in Sickle Cell Anemia ManmanLi International Journal of Molecular Medical Science, 2024, Vol. 14, No. 4, 203-215 Genomic Studies and Personalized Treatment of Depression Tiantian Li, Jie Zhang International Journal of Molecular Medical Science, 2024, Vol. 14, No. 4, 216-226 The Epigenetic Landscape of Colon Cancer: Role of DNA Methylatio Qunyu Hu, Guolin Zhao, Dongwei Zhang International Journal of Molecular Medical Science, 2024, Vol. 14, No. 4, 227-238 Unveiling Cellular Heterogeneity in Colorectal Cancer Through Single-Cell Sequencing Jiahao Zhu, Jie Lian, Haibo Lu International Journal of Molecular Medical Science, 2024, Vol. 14, No. 4, 239-251 Prospects of Gene Therapy in Alzheimer's Disease Yuchuan Yang, Xiaoying Xu International Journal of Molecular Medical Science, 2024, Vol. 14, No. 4, 252-263
International Journal of Molecular Medical Science, 2024, Vol.14, No.4, 203-215 http://medscipublisher.com/index.php/ijmms 203 Systematic Review Open Access Epigenetic Regulatory Mechanisms in Sickle Cell Anemia ManmanLi Hainan Institute of Biotechnology, Haikou, 570206, Hainan, China Corresponding email: manan.li@hibio.org International Journal of Molecular Medical Science, 2024, Vol.14, No.4 doi: 10.5376/ijmms.2024.14.0023 Received: 23 May, 2024 Accepted: 28 Jun., 2024 Published: 09 Jul., 2024 Copyright © 2024 Li, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Li M.M., 2024, Epigenetic regulatory mechanisms in sickle cell anemia, International Journal of Molecular Medical Science, 14(4): 203-215 (doi: 10.5376/ijmms.2024.14.0023) Abstract Epigenetics plays a critical role in gene regulation and disease development by influencing gene expression without altering the DNA sequence. Sickle Cell Anemia (SCA) is a genetic disorder caused by a single gene mutation, and epigenetic mechanisms are crucial in modulating the pathophysiology of SCA. This study explores the role of epigenetics in SCA, with a particular focus on the epigenetic regulation of fetal hemoglobin (HbF), histone modifications, DNA methylation, and the role of non-coding RNAs. The study also examines how these epigenetic regulatory mechanisms influence the clinical manifestations of SCA and discusses the potential of these mechanisms as therapeutic targets. Additionally, the potential functions of non-coding RNAs in regulating gene expression in SCA are summarized. The findings indicate that the epigenetic regulation of HbF expression is essential in alleviating SCA symptoms, while histone modifications and DNA methylation play significant roles in regulating gene expression in SCA. Furthermore, non-coding RNAs are also involved in the gene regulatory networks of SCA. By delving into the epigenetic regulatory mechanisms in SCA, this study provides a theoretical basis for developing novel therapeutic strategies. These insights not only contribute to understanding the molecular basis of SCA but also offer new perspectives for developing epigenetic therapies targeting HbF, thereby improving the prognosis of SCA patients. Keywords Sickle cell anemia; Epigenetic regulation; Fetal hemoglobin; Histone modifications; DNA methylationg 1 Introduction Sickle Cell Anemia (SCA) is a hereditary blood disorder caused by a mutation in the β-globin gene, leading to the production of abnormal hemoglobin known as hemoglobin S (HbS). This mutation results in the polymerization of HbS under deoxygenated conditions, causing red blood cells (RBCs) to assume a sickled shape. These sickled RBCs are rigid and fragile, leading to hemolytic anemia and various complications such as vaso-occlusive crises, chronic inflammation, and organ damage (Kato et al., 2018; Nader et al., 2020; Nader et al., 2021). The disease is characterized by a wide range of acute and chronic complications, including pain episodes, acute chest syndrome, stroke, and chronic kidney disease (Kato et al., 2018; Sundd et al., 2019). Epigenetics refers to heritable changes in gene expression that do not involve alterations in the DNA sequence. These changes can be influenced by various factors, including environmental stimuli, and can significantly impact disease progression and severity (Mason, 2024). In the context of SCA, epigenetic mechanisms such as DNA methylation, histone modification, and non-coding RNA regulation play crucial roles in modulating the expression of genes involved in inflammation, oxidative stress, and vascular function (Sundd et al., 2019; Conran and Paula, 2020). These epigenetic modifications can influence the clinical phenotype of SCA, potentially offering new avenues for therapeutic intervention. Understanding the epigenetic regulatory mechanisms in Sickle Cell Anemia (SCA) is crucial. It provides insights into the differences in disease severity and treatment responses among patients. Moreover, it offers possibilities for developing strategies to modify epigenetic marks, which could alleviate disease symptoms and improve patient outcomes. Research into the epigenetics of SCA also contributes to the broader field of epigenetics, revealing how genetic and environmental factors interact to influence complex diseases (Inusa et al., 2019; Conran and Paula, 2020). This study comprehensively reviews the current understanding of epigenetic regulatory mechanisms in SCA. It includes exploring how epigenetic modifications influence disease progression, the potential of epigenetic
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
International Journal of Molecular Medical Science, 2024, Vol.14, No.4, 203-215 http://medscipublisher.com/index.php/ijmms 205 the central event in the molecular pathogenesis of SCA, leading to the characteristic clinical manifestations of the disease. Figure 1 The Promoting Effect of NRF2 on the Expression of DNMT1 and DNMT3b (Adapted from Silva-Llanes et al., 2023) Image caption: A: qPCR was used to measure the mRNA levels of Dnmt1, Dnmt3a, and Dnmt3b in Nfe2l2+/+ and Nfe2l2−/ − mouse embryonic fibroblasts (MEFs); B: Western blot analysis was conducted to assess the protein levels of DNMT1, DNMT3a, and DNMT3b in the same samples, followed by densitometric quantification; C: Time-course analysis of the changes in mRNA levels of Dnmt1, Dnmt3a, and Dnmt3b in hippocampal HT22 cells after DMF treatment; D: Western blot analysis of the corresponding DNMT1, DNMT3a, and DNMT3b protein levels, with densitometric quantification (Adapted from Silva-Llanes et al., 2023) 3.2 Pathophysiology of SCA The pathophysiology of SCA is complex and multifaceted. The sickling of red blood cells results in chronic hemolysis and vaso-occlusion, which in turn lead to ischemia-reperfusion injury, endothelial dysfunction, and chronic inflammation. These processes contribute to the wide range of complications seen in SCA, including pain crises, organ damage, and increased risk of infections. Oxidative stress plays a significant role in the pathophysiology, as sickled cells are more prone to oxidative damage, which exacerbates hemolysis and inflammation (Figure 2) (Sangokoya et al., 2010; Silva and Faustino, 2023). Additionally, the disease is phenotypically heterogeneous, influenced by both genetic and environmental factors, which modulate the severity and presentation of symptoms (Steinberg and Sebastiani, 2012; Silva and Faustino, 2023). Silva and Faustino (2023) investigated the mechanisms of oxidative stress in sickle cell disease, illustrating the pathological processes from the formation of sickled red blood cells to vascular occlusion and ultimately organ
International Journal of Molecular Medical Science, 2024, Vol.14, No.4, 203-215 http://medscipublisher.com/index.php/ijmms 206 ischemia. Figure 2 reveals how HbS induces membrane damage and hemolysis, leading to nitric oxide (NO) depletion and oxidative stress, which in turn causes vascular dysfunction and thrombosis, resulting in ischemic injury. By elucidating this mechanism, the study emphasizes the potential of targeting oxidative stress and related molecular pathways in treating SCD to slow disease progression and reduce the risk of complications. Figure 2 Pathways of Oxidative Stress Mechanisms in Sickle Cell Disease (Adapted from Silva and Faustino, 2023) Image caption: The image illustrates the central role of oxidative stress in the progression of Sickle Cell Disease (SCD). In low-oxygen conditions, hemoglobin S (HbS) in sickle-shaped red blood cells (SSRBCs) polymerizes, leading to the formation of sickle cells, membrane damage, and hemolysis. The released Hb further reduces nitric oxide (NO) levels, promoting vasoconstriction and endothelial cell activation, which leads to vascular occlusion (thrombosis). Vascular occlusion and hypoxia ultimately result in ischemia and organ damage, particularly triggering ischemic strokes in the brain (Adapted from Silva and Faustino, 2023). 3.3 Current genetic understanding Recent advances in genetic research have provided deeper insights into the genetic modifiers and regulatory mechanisms that influence the severity of SCA. One of the key genetic factors is the concentration of fetal hemoglobin (HbF), which can ameliorate the severity of SCA by inhibiting HbS polymerization. Genetic variants that delay the switch from fetal to adult hemoglobin, such as those affecting the BCL11A gene, have been identified as potential therapeutic targets (Chen et al., 2017; Williams and Thein, 2018). Additionally, the presence of co-inherited α-thalassemia can modulate the clinical phenotype of SCA by reducing the overall hemoglobin concentration and thereby decreasing the likelihood of vaso-occlusion (Steinberg and Sebastiani, 2012). Epigenetic factors, such as DNA methylation and histone modifications, also play a crucial role in the regulation of gene expression in SCA, influencing the disease's progression and response to treatment (Wang et al., 2020; Bao et al., 2021; Lê et al., 2023). These genetic and epigenetic insights are paving the way for novel therapeutic approaches, including gene therapy and targeted drug development, aimed at reactivating HbF production and correcting the underlying genetic defect (Williams and Thein, 2018; Wang et al., 2020; Bao et al., 2021). 4 Epigenetic Modulation of Fetal Hemoglobin (HbF) in Sickle Cell Anemia 4.1 Role of HbF in ameliorating SCA symptoms Fetal hemoglobin (HbF) plays a crucial role in mitigating the symptoms of sickle cell anemia (SCA). HbF can inhibit the polymerization of deoxyhemoglobin S (HbS), which is responsible for the sickling of red blood cells. This inhibition helps to reduce the vaso-occlusive crises and hemolytic anemia that characterize SCA (Bae et al., 2012; Steinberg, 2020). The protective effect of HbF is evident in patients with higher HbF levels, who generally exhibit milder disease phenotypes. For instance, individuals with the Senegal and Saudi-Indian haplotypes, which are associated with higher HbF levels, tend to have less severe clinical manifestations of SCA (Akinsheye et al., 2011).
International Journal of Molecular Medical Science, 2024, Vol.14, No.4, 203-215 http://medscipublisher.com/index.php/ijmms 207 Moreover, the distribution of HbF among erythrocytes is a significant factor in its protective role. Patients with a higher proportion of HbF-containing erythrocytes experience fewer complications compared to those with a lower proportion, even if their total HbF levels are similar (Steinberg, 2020). This differential distribution underscores the importance of not just the quantity but also the cellular distribution of HbF in ameliorating SCA symptoms. 4.2 Epigenetic regulation of HbF expression The expression of HbF is regulated by several genetic and epigenetic mechanisms. Key genetic loci such as BCL11A, HBS1L-MYB, and the β-globin gene cluster play pivotal roles in modulating HbF levels (Bae et al., 2012; Sales et al., 2022). Epigenetic modifications, including DNA methylation and histone modifications, also significantly influence HbF expression. For example, the silencing of the BCL11A gene, a known repressor of γ-globin gene expression, can lead to increased HbF levels (Métais et al., 2019; Quagliano et al., 2022). MicroRNAs (miRNAs) are another layer of epigenetic regulation affecting HbF expression. For instance, miR-144 has been shown to silence the NRF2 gene, which in turn represses γ-globin transcription. Inhibition of miR-144 can reverse this effect, thereby increasing HbF levels (Li et al., 2019). These findings highlight the complex interplay of genetic and epigenetic factors in the regulation of HbF, offering multiple potential targets for therapeutic intervention. 4.3 Therapeutic strategies targeting HbF Several therapeutic strategies aim to increase HbF levels to treat SCA. Pharmacological agents like hydroxyurea have been widely used to induce HbF production. However, the response to hydroxyurea varies among patients, partly due to genetic polymorphisms that affect drug efficacy and toxicity. Genetic studies have identified single-nucleotide polymorphisms (SNPs) in genes such as BCL11A that influence the response to hydroxyurea, suggesting that personalized medicine approaches could optimize treatment outcomes (Sales et al., 2022). Gene editing technologies, particularly CRISPR/Cas9, offer promising avenues for permanently increasing HbF levels. By targeting and disrupting repressor elements in the γ-globin gene promoters, such as those bound by BCL11A, researchers have successfully induced therapeutic levels of HbF in preclinical models (Métais et al., 2019; Quagliano et al., 2022). These advances in gene editing not only provide a potential cure for SCA but also highlight the importance of understanding the genetic and epigenetic regulation of HbF for developing effective therapies. 5 Histone Modifications and Sickle Cell Anemia 5.1 Histone acetylation and deacetylation Histone acetylation and deacetylation are critical processes in the regulation of gene expression, impacting various diseases, including sickle cell anemia. Histone acetylation, typically associated with gene activation, is mediated by histone acetyltransferases (HATs), while histone deacetylation, associated with gene repression, is mediated by histone deacetylases (HDACs). The balance between these opposing activities determines the chromatin state and, consequently, gene expression patterns. In the context of sickle cell anemia, the modulation of histone acetylation has shown potential therapeutic benefits. For instance, HDAC inhibitors (HDIs) have been explored for their ability to reactivate fetal hemoglobin (HbF) production, which can ameliorate the symptoms of sickle cell disease by inhibiting the polymerization of sickle hemoglobin (HbS) (Kelly et al., 2010; Bajbouj et al., 2021). The therapeutic potential of HDIs is supported by their efficacy in other diseases, such as cancer and cardiovascular diseases, where they modulate gene expression to counteract disease progression (Pons et al., 2008; Knethen et al., 2020). 5.2 Histone methylation Histone methylation is another crucial epigenetic modification that can either activate or repress gene transcription, depending on the specific histone residues and the number of methyl groups added. This modification is carried out by histone methyltransferases (HMTs) and reversed by histone demethylases (HDMTs).
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
International Journal of Molecular Medical Science, 2024, Vol.14, No.4, 203-215 http://medscipublisher.com/index.php/ijmms 209 microRNAs (miRNAs), long non-coding RNAs (lncRNAs), piwi-interacting RNAs (piRNAs), and others. They are involved in processes such as chromatin remodeling, DNA methylation, and histone modification, which are essential for maintaining cellular function and identity (Zhou et al., 2010; Peschansky and Wahlestedt, 2014; Wei et al., 2014). The majority of human transcripts are non-coding, highlighting their significant role in the regulation of gene expression (Zhou et al., 2010). 7.2 miRNAs in sickle cell anemia (SCA) MicroRNAs (miRNAs) are small ncRNAs that typically function by binding to complementary sequences on target mRNAs, leading to their degradation or translational repression. In the context of Sickle Cell Anemia (SCA), miRNAs have been shown to influence the expression of genes involved in erythropoiesis and hemoglobin switching. Dysregulation of specific miRNAs can contribute to the pathophysiology of SCA by affecting the balance between fetal and adult hemoglobin, thus impacting the severity of the disease (Wei et al., 2014; Pathania et al., 2021). For instance, certain miRNAs may target transcription factors or other regulatory proteins that are crucial for the expression of fetal hemoglobin, which has been shown to ameliorate the symptoms of SCA. 7.3 Therapeutic potential of non-coding RNAs The therapeutic potential of ncRNAs in SCA is a promising area of research. Given their regulatory roles, ncRNAs can be targeted to modulate gene expression and epigenetic states beneficially. For example, miRNA mimics or inhibitors can be designed to restore normal gene expression patterns disrupted in SCA. Similarly, lncRNAs, which can act as scaffolds for chromatin-modifying complexes or decoys for miRNAs, offer another layer of therapeutic intervention (Forrest and Khalil, 2017; Zhang et al., 2020; Tachiwana and Saitoh, 2021). The ability to modulate ncRNA activity opens up new avenues for developing treatments that can potentially correct the underlying genetic and epigenetic abnormalities in SCA (Peschansky and Wahlestedt, 2014; Huang et al., 2020). 8 Current and Emerging Epigenetic Therapies for Sickle Cell Anemia 8.1 Histone deacetylase inhibitors (HDACis) Histone deacetylase inhibitors (HDACis) have shown promise in the treatment of various diseases, including cancer and potentially sickle cell anemia, by modulating gene expression through chromatin remodeling. HDACis such as suberoylanilide hydroxamic acid (SAHA), trichostatin A, and MS-27-275 have been studied extensively for their ability to alter gene expression profiles, leading to the upregulation of tumor suppressor genes and the downregulation of genes involved in cell cycle and apoptosis (Glaser et al., 2003). SAHA, in particular, has demonstrated significant anticancer activity in clinical trials and has been shown to induce changes in the acetylation and methylation of core histones, thereby increasing the accessibility of the p21 (WAF1) promoter to transcriptional machinery (Gui et al., 2004). Additionally, HDACis have been found to decrease the stability of DNMT3B mRNA, leading to reduced de novo DNA methylation activity, which further underscores their potential in epigenetic therapy (Xiong et al., 2005). 8.2 DNA methyltransferase inhibitors DNA methyltransferase inhibitors (DNMTis) are another class of epigenetic agents that have garnered attention for their ability to reverse aberrant DNA methylation patterns associated with various diseases. These inhibitors, such as 5-aza-2'-deoxycytidine (ADC), have been shown to reactivate silenced genes by demethylating DNA. The combination of DNMTis with HDACis has been particularly effective, as HDACis can enhance the demethylating effects of DNMTis, leading to a more pronounced reactivation of silenced genes (Xiong et al., 2005). This synergistic effect has been observed in various cancer models and holds potential for the treatment of sickle cell anemia by reactivating fetal hemoglobin (HbF) production, which can ameliorate the symptoms of the disease (Xu, and Yu, 2020). 8.3 Gene editing and epigenome editing technologies Recent advancements in gene editing and epigenome editing technologies, such as CRISPR/Cas9 and CRISPR/dCas9, have opened new avenues for the treatment of genetic disorders, including sickle cell anemia. These technologies allow for precise modifications of the genome and epigenome, enabling the correction of
International Journal of Molecular Medical Science, 2024, Vol.14, No.4, 203-215 http://medscipublisher.com/index.php/ijmms 210 specific genetic mutations or the targeted regulation of gene expression. For instance, CRISPR/Cas9 has been used to correct the sickle cell mutation in hematopoietic stem cells, offering a potential curative approach for the disease. Additionally, CRISPR/dCas9-based epigenome editing can be employed to modulate the expression of key genes involved in hemoglobin production, such as BCL11A, thereby increasing HbF levels and reducing the severity of sickle cell anemia (Huang et al., 2019; Rabal et al., 2021). 9 Challenges and Future Directions 9.1 Complexity of epigenetic regulation in SCA The regulation of gene expression through epigenetic mechanisms is inherently complex, involving a multitude of chromatin-modifying enzymes and coregulator complexes that operate in a context-dependent manner. This complexity is exemplified in the regulation of erythropoiesis, where a series of β-globin genes are sequentially activated and silenced, providing a model for coordinated gene expression (Wang et al., 2020). The intricate interplay between DNA methylation, histone modifications, and non-coding RNAs further complicates our understanding of epigenetic regulation in sickle cell anemia (SCA) (Delcuve et al., 2009; Binnie et al., 2020). The challenge lies in deciphering these multifaceted interactions to identify precise therapeutic targets that can modulate gene expression beneficially in SCA. 9.2 Translational research gaps Despite significant advances in understanding the epigenetic mechanisms underlying various diseases, there remains a substantial gap in translating these findings into clinical applications for SCA. While epigenetic therapies have shown promise in cancer treatment by targeting DNA methylation and histone modifications (Dawson, 2017; Cheng et al., 2019; Hogg et al., 2020), similar approaches in SCA are still in their infancy. The potential to manipulate the β-globin locus to favor the activation of fetal hemoglobin over mutated adult β-globin genes offers a promising therapeutic avenue (Ginder, 2015; Wang et al., 2020). However, the translation of these strategies from bench to bedside requires rigorous clinical trials and a deeper understanding of the long-term effects of epigenetic modifications in patients with SCA. 9.3 Potential for personalized epigenetic therapies The future of epigenetic therapies in SCA lies in the potential for personalized medicine. By leveraging the reversibility of epigenetic modifications, it is possible to develop tailored treatments that specifically target the unique epigenetic landscape of individual patients (Dawson and Kouzarides, 2012; Ding et al., 2021; Licht and Bennett, 2021). This approach could enhance the efficacy of existing treatments and reduce adverse effects by precisely modulating gene expression. For instance, small-molecule inhibitors of epigenetic regulators could be used to reactivate silenced fetal globin genes, thereby ameliorating the symptoms of SCA (Ginder, 2015; Wang et al., 2020). The development of such personalized therapies will require comprehensive epigenomic profiling and a robust understanding of the patient-specific epigenetic alterations that contribute to disease pathology (Yang, 2024). 10 Concluding Remarks Epigenetic regulatory mechanisms play a crucial role in the pathogenesis and progression of various diseases, including sickle cell anemia. Key insights from the reviewed literature highlight the importance of DNA methylation, histone modifications, and non-coding RNAs in gene expression regulation. These mechanisms are pivotal in maintaining cellular identity and function, and their dysregulation can lead to significant pathological conditions. For instance, histone modifications such as acetylation and methylation are critical in regulating chromatin structure and gene expression, and their aberrations are linked to diseases like cancer and sepsis. Additionally, the interplay between epigenetic modifications and transcription factors is essential in hematopoietic stem cell differentiation and function, which is relevant to understanding the molecular underpinnings of sickle cell anemia. The findings underscore the need for further research into the specific epigenetic alterations associated with sickle cell anemia. Future studies should focus on identifying the precise epigenetic changes that occur in sickle cell disease and how these modifications influence gene expression and disease progression. Investigating the
International Journal of Molecular Medical Science, 2024, Vol.14, No.4, 203-215 http://medscipublisher.com/index.php/ijmms 211 potential of epigenetic therapies, such as the use of DNA methylation inhibitors or histone deacetylase inhibitors, could provide new avenues for treatment. Moreover, exploring the crosstalk between epigenetic and epitranscriptomic mechanisms could offer deeper insights into the complex regulatory networks governing gene expression in sickle cell anemia. In conclusion, the role of epigenetic regulatory mechanisms in sickle cell anemia is a promising area of research that holds potential for novel therapeutic strategies. The reversible nature of epigenetic modifications presents an opportunity for developing targeted treatments that can modify disease outcomes. As our understanding of these mechanisms deepens, it is imperative to translate these insights into clinical applications that can improve the quality of life for individuals with sickle cell anemia. Continued interdisciplinary research efforts will be essential in unraveling the complexities of epigenetic regulation and harnessing this knowledge for therapeutic benefit. Acknowledgments Thank you to the peer reviewers for providing feedback on this study. Conflict of Interest Disclosure The author affirms that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. References Akinsheye I., Alsultan A., Solovieff N., Ngo D., Baldwin C., Sebastiani P., Chui D., and Steinberg M., 2011, Fetal hemoglobin in sickle cell anemia, Blood, 118(1): 19-27. https://doi.org/10.1182/blood-2011-03-325258 PMid:21490337 PMCid:PMC3139383 Alagia A., and Gullerová M., 2022, The methylation game: epigenetic and epitranscriptomic dynamics of 5-methylcytosine, Frontiers in Cell and Developmental Biology, 10: 915685. https://doi.org/10.3389/fcell.2022.915685 PMid:35721489 PMCid:PMC9204050 Bae H., Baldwin C., Sebastiani P., Telen M., Ashley-Koch A., Garrett M., Hooper W., Bean C., DeBaun M., Arking D., Bhatnagar P., Casella J., Keefer J., Barron-Casella E., Gordeuk V., Kato G., Minniti C., Taylor J., Campbell A., Luchtman-Jones L., Hoppe C., Gladwin M., Zhang Y., and Steinberg M., 2012, Meta-analysis of 2040 sickle cell anemia patients: BCL11A and HBS1L-MYB are the major modifiers of HbF in African Americans, Blood, 120(9): 1961-1962. https://doi.org/10.1182/blood-2012-06-432849 PMid:22936743 PMCid:PMC3433099 Bajbouj K., Al-Ali A., Ramakrishnan R., Saber-Ayad M., and Hamid Q., 2021, Histone modification in NSCLC: molecular mechanisms and therapeutic targets, International Journal of Molecular Sciences, 22(21): 11701. https://doi.org/10.3390/ijms222111701 PMid:34769131 PMCid:PMC8584007 Bao X., Zhang X., Wang L., Wang Z., Huang J., Zhang Q., Ye Y., Liu Y., Chen D., Zuo Y., Liu Q., Xu P., Huang B., Fang J., Lao J., Feng X., Li Y., Kurita R., Nakamura Y., Yu W., Ju C., Huang C., Mohandas N., Li D., Zhao C., and Xu X., 2021, Epigenetic inactivation of ERF reactivates γ-globin expression in β-thalassemia, American Journal of Human Genetics, 108(4): 709-721. https://doi.org/10.1016/j.ajhg.2021.03.005 PMid:33735615 PMCid:PMC8059375 Binnie A., Tsang J., Hu P., Carrasqueiro G., Castelo-Branco P., and Santos C., 2020, Epigenetics of sepsis, Critical Care Medicine, 48: 745-756. https://doi.org/10.1097/CCM.0000000000004247 PMid:32167492 Breiling A., and Lyko F., 2015, Epigenetic regulatory functions of DNA modifications: 5-methylcytosine and beyond, Epigenetics & Chromatin, 8: 24 https://doi.org/10.1186/s13072-015-0016-6 PMid:26195987 PMCid:PMC4507326 Carbajo-García M., Miguel-Gómez L., Juárez-Barber E., Trelis A., Monleón J., Pellicer A., Flanagan J., and Ferrero H., 2022, Deciphering the role of histone modifications in uterine leiomyoma: acetylation of H3K27 regulates the expression of genes involved in proliferation, cell signaling, cell transport, Angiogenesis and Extracellular Matrix Formation, Biomedicines, 10(6): 1279. https://doi.org/10.3390/biomedicines10061279 PMid:35740301 PMCid:PMC9219820 Chen D., Zuo Y., Zhang X., Ye Y., Bao X., Huang H., Tepakhan W., Wang L., Ju J., Chen G., Zheng M., Liu D., Huang S., Zong L., Li C., Chen Y., Zheng C., Shi L., Zhao Q., Wu Q., Fucharoen S., Zhao C., and Xu X., 2017, A genetic variant ameliorates β-thalassemia severity by epigenetic-mediated elevation of human fetal hemoglobin expression, American Journal of Human genetics, 101(1): 130-138.
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