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1
Zhang, Xiaolin, Zhen Dong, and Hongjuan Cui. "Interplay between Epigenetics and Cellular Metabolism in Colorectal Cancer." Biomolecules 11, no. 10 (September 25, 2021): 1406. http://dx.doi.org/10.3390/biom11101406.
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Cellular metabolism alterations have been recognized as one of the most predominant hallmarks of colorectal cancers (CRCs). It is precisely regulated by many oncogenic signaling pathways in all kinds of regulatory levels, including transcriptional, post-transcriptional, translational and post-translational levels. Among these regulatory factors, epigenetics play an essential role in the modulation of cellular metabolism. On the one hand, epigenetics can regulate cellular metabolism via directly controlling the transcription of genes encoding metabolic enzymes of transporters. On the other hand, epigenetics can regulate major transcriptional factors and signaling pathways that control the transcription of genes encoding metabolic enzymes or transporters, or affecting the translation, activation, stabilization, or translocation of metabolic enzymes or transporters. Interestingly, epigenetics can also be controlled by cellular metabolism. Metabolites not only directly influence epigenetic processes, but also affect the activity of epigenetic enzymes. Actually, both cellular metabolism pathways and epigenetic processes are controlled by enzymes. They are highly intertwined and are essential for oncogenesis and tumor development of CRCs. Therefore, they are potential therapeutic targets for the treatment of CRCs. In recent years, both epigenetic and metabolism inhibitors are studied for clinical use to treat CRCs. In this review, we depict the interplay between epigenetics and cellular metabolism in CRCs and summarize the underlying molecular mechanisms and their potential applications for clinical therapy.
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Kringel, Dario, Sebastian Malkusch, and Jörn Lötsch. "Drugs and Epigenetic Molecular Functions. A Pharmacological Data Scientometric Analysis." International Journal of Molecular Sciences 22, no. 14 (July 6, 2021): 7250. http://dx.doi.org/10.3390/ijms22147250.
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Interactions of drugs with the classical epigenetic mechanism of DNA methylation or histone modification are increasingly being elucidated mechanistically and used to develop novel classes of epigenetic therapeutics. A data science approach is used to synthesize current knowledge on the pharmacological implications of epigenetic regulation of gene expression. Computer-aided knowledge discovery for epigenetic implications of current approved or investigational drugs was performed by querying information from multiple publicly available gold-standard sources to (i) identify enzymes involved in classical epigenetic processes, (ii) screen original biomedical scientific publications including bibliometric analyses, (iii) identify drugs that interact with epigenetic enzymes, including their additional non-epigenetic targets, and (iv) analyze computational functional genomics of drugs with epigenetic interactions. PubMed database search yielded 3051 hits on epigenetics and drugs, starting in 1992 and peaking in 2016. Annual citations increased to a plateau in 2000 and show a downward trend since 2008. Approved and investigational drugs in the DrugBank database included 122 compounds that interacted with 68 unique epigenetic enzymes. Additional molecular functions modulated by these drugs included other enzyme interactions, whereas modulation of ion channels or G-protein-coupled receptors were underrepresented. Epigenetic interactions included (i) drug-induced modulation of DNA methylation, (ii) drug-induced modulation of histone conformations, and (iii) epigenetic modulation of drug effects by interference with pharmacokinetics or pharmacodynamics. Interactions of epigenetic molecular functions and drugs are mutual. Recent research activities on the discovery and development of novel epigenetic therapeutics have passed successfully, whereas epigenetic effects of non-epigenetic drugs or epigenetically induced changes in the targets of common drugs have not yet received the necessary systematic attention in the context of pharmacological plasticity.
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Ramarao-Milne, Priya, Olga Kondrashova, Sinead Barry, John D. Hooper, Jason S. Lee, and Nicola Waddell. "Histone Modifying Enzymes in Gynaecological Cancers." Cancers 13, no. 4 (February 16, 2021): 816. http://dx.doi.org/10.3390/cancers13040816.
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Genetic and epigenetic factors contribute to the development of cancer. Epigenetic dysregulation is common in gynaecological cancers and includes altered methylation at CpG islands in gene promoter regions, global demethylation that leads to genome instability and histone modifications. Histones are a major determinant of chromosomal conformation and stability, and unlike DNA methylation, which is generally associated with gene silencing, are amenable to post-translational modifications that induce facultative chromatin regions, or condensed transcriptionally silent regions that decondense resulting in global alteration of gene expression. In comparison, other components, crucial to the manipulation of chromatin dynamics, such as histone modifying enzymes, are not as well-studied. Inhibitors targeting DNA modifying enzymes, particularly histone modifying enzymes represent a potential cancer treatment. Due to the ability of epigenetic therapies to target multiple pathways simultaneously, tumours with complex mutational landscapes affected by multiple driver mutations may be most amenable to this type of inhibitor. Interrogation of the actionable landscape of different gynaecological cancer types has revealed that some patients have biomarkers which indicate potential sensitivity to epigenetic inhibitors. In this review we describe the role of epigenetics in gynaecological cancers and highlight how it may exploited for treatment.
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Ruoß, Marc, Georg Damm, Massoud Vosough, Lisa Ehret, Carl Grom-Baumgarten, Martin Petkov, Silvio Naddalin, et al. "Epigenetic Modifications of the Liver Tumor Cell Line HepG2 Increase Their Drug Metabolic Capacity." International Journal of Molecular Sciences 20, no. 2 (January 16, 2019): 347. http://dx.doi.org/10.3390/ijms20020347.
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Although human liver tumor cells have reduced metabolic functions as compared to primary human hepatocytes (PHH) they are widely used for pre-screening tests of drug metabolism and toxicity. The aim of the present study was to modify liver cancer cell lines in order to improve their drug-metabolizing activities towards PHH. It is well-known that epigenetics is strongly modified in tumor cells and that epigenetic regulators influence the expression and function of Cytochrome P450 (CYP) enzymes through altering crucial transcription factors responsible for drug-metabolizing enzymes. Therefore, we screened the epigenetic status of four different liver cancer cell lines (Huh7, HLE, HepG2 and AKN-1) which were reported to have metabolizing drug activities. Our results showed that HepG2 cells demonstrated the highest similarity compared to PHH. Thus, we modified the epigenetic status of HepG2 cells towards ‘normal’ liver cells by 5-Azacytidine (5-AZA) and Vitamin C exposure. Then, mRNA expression of Epithelial-mesenchymal transition (EMT) marker SNAIL and CYP enzymes were measured by PCR and determinate specific drug metabolites, associated with CYP enzymes by LC/MS. Our results demonstrated an epigenetic shift in HepG2 cells towards PHH after exposure to 5-AZA and Vitamin C which resulted in a higher expression and activity of specific drug metabolizing CYP enzymes. Finally, we observed that 5-AZA and Vitamin C led to an increased expression of Hepatocyte nuclear factor 4α (HNF4α) and E-Cadherin and a significant down regulation of Snail1 (SNAIL), the key transcriptional repressor of E-Cadherin. Our study shows, that certain phase I genes and their enzyme activities are increased by epigenetic modification in HepG2 cells with a concomitant reduction of EMT marker gene SNAIL. The enhancing of liver specific functions in hepatoma cells using epigenetic modifiers opens new opportunities for the usage of cell lines as a potential liver in vitro model for drug testing and development.
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Maleszewska, Marta, Bartosz Wojtas, Bartlomiej Gielniewski, Shamba Mondal, Jakub Mieczkowski, Michal Dabrowski, Janusz Siedlecki, et al. "ECOA-6. Genomic and transcriptomic analyses reveal diverse mechanisms responsible for deregulation of epigenetic enzyme/modifier expression in glioblastoma." Neuro-Oncology Advances 3, Supplement_2 (July 1, 2021): ii2. http://dx.doi.org/10.1093/noajnl/vdab070.006.
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Abstract Malignant gliomas represent over 70% of primary brain tumors and the most deadly is glioblastoma (GBM, WHO grade IV), due to frequent dysfunctions of tumor suppressors or/and oncogenes. Recent whole genome studies of gliomas demonstrated that besides genetic alterations, epigenetic dysfunctions contribute to tumor development and progression. Alterations in genes encoding epigenetic enzyme/protein or aberrations in epigenetic modification pattern have been found in gliomas of lower grade, yet no epigenetic driver was identified in GBM. We sought to identify different mechanisms driving aberrant expression of epigenetic genes in GBM. We analyzed gene expression and coding/non-coding regions of 96 major epigenetic enzymes and chromatin modifiers in 28 GBMs, 23 benign gliomas (juvenile pilocytic astrocytomas, JPAs, WHO grade I) and 7 normal brain samples. We found a profound and global down-regulation of expression of most tested epigenetic enzymes and modifiers in GBMs when compared to normal brains and JPAs. For some genes changes in mRNA level correlated with newly identified single nucleotide variants within non-coding regulatory regions. To find a common denominator responsible for the coordinated down-regulation of expression of epigenetic enzymes/modifiers, we employed PWMEnrich tool for DNA motif scanning and enrichment analysis. Among others, we discovered the presence of high affinity motifs for the E2F1/E2F4 transcription factors, within the promoters of the epigenetic enzyme/modifier encoding genes. Knockdown of the E2F1/E2F4 expression affected the expression of a set of epigenetic enzymes/modifiers. Altogether, our results reveal a novel epigenetic-related pathway by which E2F1/E2F4 factors contribute to glioma pathogenesis and indicate novel targets for glioma therapy. Supported by a National Science Centre grant 2013/09/B/NZ3/01402 (MM).
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Amsalem, Zohar, Tasleem Arif, Anna Shteinfer-Kuzmine, Vered Chalifa-Caspi, and Varda Shoshan-Barmatz. "The Mitochondrial Protein VDAC1 at the Crossroads of Cancer Cell Metabolism: The Epigenetic Link." Cancers 12, no. 4 (April 22, 2020): 1031. http://dx.doi.org/10.3390/cancers12041031.
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Carcinogenesis is a complicated process that involves the deregulation of epigenetics, resulting in cellular transformational events, such as proliferation, differentiation, and metastasis. Most chromatin-modifying enzymes utilize metabolites as co-factors or substrates and thus are directly dependent on such metabolites as acetyl-coenzyme A, S-adenosylmethionine, and NAD+. Here, we show that using specific siRNA to deplete a tumor of VDAC1 not only led to reprograming of the cancer cell metabolism but also altered several epigenetic-related enzymes and factors. VDAC1, in the outer mitochondrial membrane, controls metabolic cross-talk between the mitochondria and the rest of the cell, thus regulating the metabolic and energetic functions of mitochondria, and has been implicated in apoptotic-relevant events. We previously demonstrated that silencing VDAC1 expression in glioblastoma (GBM) U-87MG cell-derived tumors, resulted in reprogramed metabolism leading to inhibited tumor growth, angiogenesis, epithelial–mesenchymal transition and invasiveness, and elimination of cancer stem cells, while promoting the differentiation of residual tumor cells into neuronal-like cells. These VDAC1 depletion-mediated effects involved alterations in transcription factors regulating signaling pathways associated with cancer hallmarks. As the epigenome is sensitive to cellular metabolism, this study was designed to assess whether depleting VDAC1 affects the metabolism–epigenetics axis. Using DNA microarrays, q-PCR, and specific antibodies, we analyzed the effects of si-VDAC1 treatment of U-87MG-derived tumors on histone modifications and epigenetic-related enzyme expression levels, as well as the methylation and acetylation state, to uncover any alterations in epigenetic properties. Our results demonstrate that metabolic rewiring of GBM via VDAC1 depletion affects epigenetic modifications, and strongly support the presence of an interplay between metabolism and epigenetics.
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Jelinek, Mary Anne. "Biochemical Assays for Epigenetic Enzymes." Genetic Engineering & Biotechnology News 36, no. 15 (September 2016): 16–17. http://dx.doi.org/10.1089/gen.36.15.08.
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Jasim, Dr Hiba Sabah. "The Role of Epigenetic Drugs in Cancer Therapy." South Asian Research Journal of Medical Sciences 4, no. 4 (August 25, 2022): 54–62. http://dx.doi.org/10.36346/sarjms.2022.v04i04.001.
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Epigenetics refers to heritable and dynamic alterations in the whole genes which present in the sequence of nucleic acids. It consider as concurrent reaction with enzymes and several molecular ingredients. Epigenetic changes can cause the incorrect start of coding genes, allowing tumor development. Epigenetic modifiers are becoming potential targets in numerous malignant tumor therapies since they are sensitive to foreign drugs. Different epigenetic medicines that were lately refined and implicated in clinical experiences using of epigenetic medicines solitary or together with immunotherapy and chemotherapy has yielded promising outcomes, containing advanced anti-cancer impact, overcoming therapy resistant, and stimulation of the immune system defense.
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Alghamdi, Bandar Ali, Intisar Mahmoud Aljohani, Bandar Ghazi Alotaibi, Muhammad Ahmed, Kholod Abduallah Almazmomi, Salman Aloufi, and Jowhra Alshamrani. "Studying Epigenetics of Cardiovascular Diseases on Chip Guide." Cardiogenetics 12, no. 3 (July 7, 2022): 218–34. http://dx.doi.org/10.3390/cardiogenetics12030021.
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Epigenetics is defined as the study of inheritable changes in the gene expressions and phenotypes that occurs without altering the normal DNA sequence. These changes are mainly due to an alteration in chromatin or its packaging, which changes the DNA accessibility. DNA methylation, histone modification, and noncoding or microRNAs can best explain the mechanism of epigenetics. There are various DNA methylated enzymes, histone-modifying enzymes, and microRNAs involved in the cause of various CVDs (cardiovascular diseases) such as cardiac hypertrophy, heart failure, and hypertension. Moreover, various CVD risk factors such as diabetes mellitus, hypoxia, aging, dyslipidemia, and their epigenetics are also discussed together with CVDs such as CHD (coronary heart disease) and PAH (pulmonary arterial hypertension). Furthermore, different techniques involved in epigenetic chromatin mapping are explained. Among these techniques, the ChIP-on-chip guide is explained with regard to its role in cardiac hypertrophy, a final form of heart failure. This review focuses on different epigenetic factors that are involved in causing cardiovascular diseases.
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Bunsick, David A., Jenna Matsukubo, and Myron R. Szewczuk. "Cannabinoids Transmogrify Cancer Metabolic Phenotype via Epigenetic Reprogramming and a Novel CBD Biased G Protein-Coupled Receptor Signaling Platform." Cancers 15, no. 4 (February 6, 2023): 1030. http://dx.doi.org/10.3390/cancers15041030.
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The concept of epigenetic reprogramming predicts long-term functional health effects. This reprogramming can be activated by exogenous or endogenous insults, leading to altered healthy and different disease states. The exogenous or endogenous changes that involve developing a roadmap of epigenetic networking, such as drug components on epigenetic imprinting and restoring epigenome patterns laid down during embryonic development, are paramount to establishing youthful cell type and health. This epigenetic landscape is considered one of the hallmarks of cancer. The initiation and progression of cancer are considered to involve epigenetic abnormalities and genetic alterations. Cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer development, including DNA methylation, histone modifications, nucleosome positioning, non-coding RNAs, and microRNA expression. Endocannabinoids are natural lipid molecules whose levels are regulated by specific biosynthetic and degradative enzymes. They bind to and activate two primary cannabinoid receptors, type 1 (CB1) and type 2 (CB2), and together with their metabolizing enzymes, form the endocannabinoid system. This review focuses on the role of cannabinoid receptors CB1 and CB2 signaling in activating numerous receptor tyrosine kinases and Toll-like receptors in the induction of epigenetic landscape alterations in cancer cells, which might transmogrify cancer metabolism and epigenetic reprogramming to a metastatic phenotype. Strategies applied from conception could represent an innovative epigenetic target for preventing and treating human cancer. Here, we describe novel cannabinoid-biased G protein-coupled receptor signaling platforms (GPCR), highlighting putative future perspectives in this field.
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Meiliana, Anna, Nurrani Mustika Dewi, and Andi Wijaya. "Nutritional Influences on Epigenetics, Aging and Disease." Indonesian Biomedical Journal 11, no. 1 (April 30, 2019): 16–29. http://dx.doi.org/10.18585/inabj.v11i1.780.
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BACKGROUND: Altered epigenetics is regarded to play quite a role in many chronic diseases including cancer, diabetes, obesity, dyslipidemia, hypertension and neurodegeneration, hence nutrition suggested to contribute in epigenetics and disease.CONTENT: Histone modifications, as a part of epigenetics mechanisms, depend on metabolites which acts as cofactors or substrates. Fluctuating levels of specific metabolites become the direct and rapid mechanisms to influence gene activity. Therefore, these metabolites may have a role as gatekeepers of chromatin, in chromatin landscape modulation as a response to key nutritional cues. Chemical modifications of histones and DNA have a critical role in epigenetic gene regulation including histone acetylation, and DNA methylation. Some enzymes add or remove such chemical modifications, and suggested to be sensitive to changes in intracellular metabolism, such as mutations in the metabolic enzymes succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH) can result in cancer.SUMMARY: As a response to their nutrient environment, organisms tend to rapidly alter their gene expression. Many evidences showed an epigenetic regulation of chromatin is coupled to the changes on metabolites levels due to this kind of response. These metabolites will lead the recruitment of transcriptional regulatory complexes to DNA, thus clearly influencing the dynamic chromatin landscape.KEYWORDS: metabolites, enzymes, epigenetics, chromatin, nutrition
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Yesayan, Alexander, Massimiliano Chetta, Bella Babayan, Tigran A. Yesayan Yesayan, Syuzanna Esoyan, and Garegin Sevoyan. "The epigenetic impact of daily diet food choices on human health and chronic diseases." Functional Foods in Health and Disease 14, no. 10 (October 25, 2024): 739–50. http://dx.doi.org/10.31989/ffhd.v14i10.1464.
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Nutrition, certain lifestyle behaviors (smoking, drug, alcohol addictions, etc.) and environment all contribute to cancer and other lines development. Similarly, epigenetic pathways are known to occur at the intersection between the generally reversible effects of lifestyle or ecological factors and the irreversible alterations that explain numerous diseases. Chemoprevention is the process of intervening in the epigenome to mitigate the detrimental effects of environmental factors or certain lifestyles before they lead to significant consequences. DNA is permanently exposed to various substances modifying both its genetic and epigenetic configuration. It’s controlled by various agents (methyl donors, sophisticated enzymes, etc.). Pesticides, artificial food additives, drugs and environmental toxins penetrating the placenta, can result in developmental program alterations and epigenetic changes in a fetus. In nutrition context, the research revealed that several foods can alter epigenetic markers. Some vitamins may alter DNA methylation patterns and histone alterations, possibly influencing gene expression and disease risk. Thus, dietary treatments may provide an epigenetic regulation, emphasizing nutrition role in preserving health and preventing illness via epigenetics Keywords: human epigenetics, epigenetic regulation of diseases, daily food ration, healthy food
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Sen, Rwik, and Christopher Barnes. "Do Transgenerational Epigenetic Inheritance and Immune System Development Share Common Epigenetic Processes?" Journal of Developmental Biology 9, no. 2 (May 12, 2021): 20. http://dx.doi.org/10.3390/jdb9020020.
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Epigenetic modifications regulate gene expression for development, immune response, disease, and other processes. A major role of epigenetics is to control the dynamics of chromatin structure, i.e., the condensed packaging of DNA around histone proteins in eukaryotic nuclei. Key epigenetic factors include enzymes for histone modifications and DNA methylation, non-coding RNAs, and prions. Epigenetic modifications are heritable but during embryonic development, most parental epigenetic marks are erased and reset. Interestingly, some epigenetic modifications, that may be resulting from immune response to stimuli, can escape remodeling and transmit to subsequent generations who are not exposed to those stimuli. This phenomenon is called transgenerational epigenetic inheritance if the epigenetic phenotype persists beyond the third generation in female germlines and second generation in male germlines. Although its primary function is likely immune response for survival, its role in the development and functioning of the immune system is not extensively explored, despite studies reporting transgenerational inheritance of stress-induced epigenetic modifications resulting in immune disorders. Hence, this review draws from studies on transgenerational epigenetic inheritance, immune system development and function, high-throughput epigenetics tools to study those phenomena, and relevant clinical trials, to focus on their significance and deeper understanding for future research, therapeutic developments, and various applications.
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Qureshi, Muhammad Zahid, Uteuliyev Yerzhan Sabitaliyevich, Marat Rabandiyarov, and Arystanbekov Talant Arystanbekuly. "Role of DNA Methyltransferases (DNMTs) in metastasis." Cellular and Molecular Biology 68, no. 1 (May 22, 2022): 226–36. http://dx.doi.org/10.14715/cmb/2022.68.1.27.
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The DNA methyltransferase (DNMT) family constitutes a conserved set of DNA-modifying enzymes which have essential functions in the modulation of epigenetics. The fundamental role of epigenetic changes in carcinogenesis and metastasis is increasingly being appreciated. DNMTs (DNMT1, DNMT3A and DNMT3B) have been shown to drive metastasis. Epigenetic machinery is installed at the target sites for the regulation of a wide variety of genes. Moreover, microRNAs, long non-coding RNAs and circular RNAs also shape the epigenetic landscape during metastasis. In this review, we have provided a snapshot of the quintessential role of DNMTs in metastasis. We also summarize how lncRNAs and circRNAs play roles in the epigenetic regulation of a myriad of genes.
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Bontempo, Paola, Lucia Capasso, Luigi De Masi, Angela Nebbioso, and Daniela Rigano. "Therapeutic Potential of Natural Compounds Acting through Epigenetic Mechanisms in Cardiovascular Diseases: Current Findings and Future Directions." Nutrients 16, no. 15 (July 24, 2024): 2399. http://dx.doi.org/10.3390/nu16152399.
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Cardiovascular diseases (CVDs) remain a leading global cause of morbidity and mortality. These diseases have a multifaceted nature being influenced by a multitude of biochemical, genetic, environmental, and behavioral factors. Epigenetic modifications have a crucial role in the onset and progression of CVD. Epigenetics, which regulates gene activity without altering the DNA’s primary structure, can modulate cardiovascular homeostasis through DNA methylation, histone modification, and non-coding RNA regulation. The effects of environmental stimuli on CVD are mediated by epigenetic changes, which can be reversible and, hence, are susceptible to pharmacological interventions. This represents an opportunity to prevent diseases by targeting harmful epigenetic modifications. Factors such as high-fat diets or nutrient deficiencies can influence epigenetic enzymes, affecting fetal growth, metabolism, oxidative stress, inflammation, and atherosclerosis. Recent studies have shown that plant-derived bioactive compounds can modulate epigenetic regulators and inflammatory responses, contributing to the cardioprotective effects of diets. Understanding these nutriepigenetic effects and their reversibility is crucial for developing effective interventions to combat CVD. This review delves into the general mechanisms of epigenetics, its regulatory roles in CVD, and the potential of epigenetics as a CVD therapeutic strategy. It also examines the role of epigenetic natural compounds (ENCs) in CVD and their potential as intervention tools for prevention and therapy.
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Zucconi, Beth E., and Philip A. Cole. "Allosteric regulation of epigenetic modifying enzymes." Current Opinion in Chemical Biology 39 (August 2017): 109–15. http://dx.doi.org/10.1016/j.cbpa.2017.05.015.
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Copeland, Robert A., Edward J. Olhava, and Margaret Porter Scott. "Targeting epigenetic enzymes for drug discovery." Current Opinion in Chemical Biology 14, no. 4 (August 2010): 505–10. http://dx.doi.org/10.1016/j.cbpa.2010.06.174.
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Sapozhnikov, Daniel M., and Moshe Szyf. "Increasing Specificity of Targeted DNA Methylation Editing by Non-Enzymatic CRISPR/dCas9-Based Steric Hindrance." Biomedicines 11, no. 5 (April 22, 2023): 1238. http://dx.doi.org/10.3390/biomedicines11051238.
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As advances in genome engineering inch the technology towards wider clinical use—slowed by technical and ethical hurdles—a newer offshoot, termed “epigenome engineering”, offers the ability to correct disease-causing changes in the DNA without changing its sequence and, thus, without some of the unfavorable correlates of doing so. In this review, we note some of the shortcomings of epigenetic editing technology—specifically the risks involved in the introduction of epigenetic enzymes—and highlight an alternative epigenetic editing strategy using physical occlusion to modify epigenetic marks at target sites without a requirement for any epigenetic enzyme. This may prove to be a safer alternative for more specific epigenetic editing.
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Li, Yinglu, Zhiming Li, and Wei-Guo Zhu. "Molecular Mechanisms of Epigenetic Regulators as Activatable Targets in Cancer Theranostics." Current Medicinal Chemistry 26, no. 8 (May 16, 2019): 1328–50. http://dx.doi.org/10.2174/0929867324666170921101947.
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Epigenetics is defined as somatically inheritable changes that are not accompanied by alterations in DNA sequence. Epigenetics encompasses DNA methylation, covalent histone modifications, non-coding RNA as well as nucleosome remodeling. Notably, abnormal epigenetic changes play a critical role in cancer development including malignant transformation, metastasis, prognosis, drug resistance and tumor recurrence, which can provide effective targets for cancer prognosis, diagnosis and therapy. Understanding these changes provide effective means for cancer diagnosis and druggable targets for better clinical applications. Histone modifications and related enzymes have been found to correlate well with cancer incidence and prognosis in recent years. Dysregulated expression or mutation of histone modification enzymes and histone modification status abnormalities have been considered to play essential roles in tumorigenesis and clinical outcomes of cancer treatment. Some of the histone modification inhibitors have been extensively employed in clinical practice and many others are still under laboratory research or pre-clinical assessment. Here we summarize the important roles of epigenetics, especially histone modifications in cancer diagnostics and therapeutics, and also discuss the developmental implications of activatable epigenetic targets in cancer theranostics.
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Lachat, Camille, Diane Bruyère, Amandine Etcheverry, Marc Aubry, Jean Mosser, Walid Warda, Michaël Herfs, et al. "EZH2 and KDM6B Expressions Are Associated with Specific Epigenetic Signatures during EMT in Non Small Cell Lung Carcinomas." Cancers 12, no. 12 (December 5, 2020): 3649. http://dx.doi.org/10.3390/cancers12123649.
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The role of Epigenetics in Epithelial Mesenchymal Transition (EMT) has recently emerged. Two epigenetic enzymes with paradoxical roles have previously been associated to EMT, EZH2 (Enhancer of Zeste 2 Polycomb Repressive Complex 2 (PRC2) Subunit), a lysine methyltranserase able to add the H3K27me3 mark, and the histone demethylase KDM6B (Lysine Demethylase 6B), which can remove the H3K27me3 mark. Nevertheless, it still remains unclear how these enzymes, with apparent opposite activities, could both promote EMT. In this study, we evaluated the function of these two enzymes using an EMT-inducible model, the lung cancer A549 cell line. ChIP-seq coupled with transcriptomic analysis showed that EZH2 and KDM6B were able to target and modulate the expression of different genes during EMT. Based on this analysis, we described INHBB, WTN5B, and ADAMTS6 as new EMT markers regulated by epigenetic modifications and directly implicated in EMT induction.
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Neff, Tobias, and Scott A. Armstrong. "Recent progress toward epigenetic therapies: the example of mixed lineage leukemia." Blood 121, no. 24 (June 13, 2013): 4847–53. http://dx.doi.org/10.1182/blood-2013-02-474833.
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Abstract The importance of epigenetic gene regulatory mechanisms in normal and cancer development is increasingly evident. Genome-wide analyses have revealed the mutation, deletion, and dysregulated expression of chromatin-modifying enzymes in a number of cancers, including hematologic malignancies. Genome-wide studies of DNA methylation and histone modifications are beginning to reveal the landscape of cancer-specific chromatin patterns. In parallel, recent genetic loss-of-function studies in murine models are demonstrating functional involvement of chromatin-modifying enzymes in malignant cell proliferation and self-renewal. Paradoxically, the same chromatin modifiers can, depending on cancer type, be either hyperactive or inactivated. Increasingly, cross talk between epigenetic pathways is being identified. Leukemias carrying MLL rearrangements are quintessential cancers driven by dysregulated epigenetic mechanisms in which fusion proteins containing N-terminal sequences of MLL require few or perhaps no additional mutations to cause human leukemia. Here, we review how recent progress in the field of epigenetics opens potential mechanism-based therapeutic avenues.
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Balch, Curt, Fang Fang, Daniela E. Matei, Tim H. M. Huang, and Kenneth P. Nephew. "Minireview: Epigenetic Changes in Ovarian Cancer." Journal of Clinical Endocrinology & Metabolism 94, no. 8 (August 1, 2009): 3098. http://dx.doi.org/10.1210/jcem.94.8.9998.
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Epigenetic aberrations, including DNA methylation, histone modifications, and micro-RNA dysregulation, are now well established in the development and progression of ovarian cancer, and their gradual accumulation is associated with advancing disease stage and grade. Epigenetic aberrations are relatively stable, associated with distinct disease subtypes, and present in circulating serum, representing promising diagnostic, prognostic, and pharmacodynamic biomarkers. In contrast to DNA mutations and deletions, aberrant gene-repressive epigenetic modifications are potentially reversible by epigenetic therapies, including inhibitors of DNA methylation or histone-modifying enzymes. Although epigenetic monotherapies have not shown activity against solid tumors, including ovarian cancer, preclinical studies suggest they will be effective when used in combination with one another or with conventional chemotherapeutics, and combinatorial epigenetic therapy regiments are being examined in cancer clinical trials. A greater understanding of the role of epigenetics in ovarian neoplasia will provide for improved interventions against this devastating malignancy.
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Balch, Curt, Fang Fang, Daniela E. Matei, Tim H. M. Huang, and Kenneth P. Nephew. "Minireview: Epigenetic Changes in Ovarian Cancer." Journal of Clinical Endocrinology & Metabolism 94, no. 9 (September 1, 2009): 3617. http://dx.doi.org/10.1210/jcem.94.9.9997.
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Epigenetic aberrations, including DNA methylation, histone modifications, and micro-RNA dysregulation, are now well established in the development and progression of ovarian cancer, and their gradual accumulation is associated with advancing disease stage and grade. Epigenetic aberrations are relatively stable, associated with distinct disease subtypes, and present in circulating serum, representing promising diagnostic, prognostic, and pharmacodynamic biomarkers. In contrast to DNA mutations and deletions, aberrant gene-repressive epigenetic modifications are potentially reversible by epigenetic therapies, including inhibitors of DNA methylation or histone-modifying enzymes. Although epigenetic monotherapies have not shown activity against solid tumors, including ovarian cancer, preclinical studies suggest they will be effective when used in combination with one another or with conventional chemotherapeutics, and combinatorial epigenetic therapy regiments are being examined in cancer clinical trials. A greater understanding of the role of epigenetics in ovarian neoplasia will provide for improved interventions against this devastating malignancy.
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Balch, Curt, Fang Fang, Daniela E. Matei, Tim H. M. Huang, and Kenneth P. Nephew. "Minireview: Epigenetic Changes in Ovarian Cancer." Endocrinology 150, no. 9 (July 2, 2009): 4003–11. http://dx.doi.org/10.1210/en.2009-0404.
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Abstract Epigenetic aberrations, including DNA methylation, histone modifications, and micro-RNA dysregulation, are now well established in the development and progression of ovarian cancer, and their gradual accumulation is associated with advancing disease stage and grade. Epigenetic aberrations are relatively stable, associated with distinct disease subtypes, and present in circulating serum, representing promising diagnostic, prognostic, and pharmacodynamic biomarkers. In contrast to DNA mutations and deletions, aberrant gene-repressive epigenetic modifications are potentially reversible by epigenetic therapies, including inhibitors of DNA methylation or histone-modifying enzymes. Although epigenetic monotherapies have not shown activity against solid tumors, including ovarian cancer, preclinical studies suggest they will be effective when used in combination with one another or with conventional chemotherapeutics, and combinatorial epigenetic therapy regiments are being examined in cancer clinical trials. A greater understanding of the role of epigenetics in ovarian neoplasia will provide for improved interventions against this devastating malignancy.
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Coker, Sharna J., Carlos C. Smith-Díaz, Rebecca M. Dyson, Margreet C. M. Vissers, and Mary J. Berry. "The Epigenetic Role of Vitamin C in Neurodevelopment." International Journal of Molecular Sciences 23, no. 3 (January 21, 2022): 1208. http://dx.doi.org/10.3390/ijms23031208.
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The maternal diet during pregnancy is a key determinant of offspring health. Early studies have linked poor maternal nutrition during gestation with a propensity for the development of chronic conditions in offspring. These conditions include cardiovascular disease, type 2 diabetes and even compromised mental health. While multiple factors may contribute to these outcomes, disturbed epigenetic programming during early development is one potential biological mechanism. The epigenome is programmed primarily in utero, and during this time, the developing fetus is highly susceptible to environmental factors such as nutritional insults. During neurodevelopment, epigenetic programming coordinates the formation of primitive central nervous system structures, neurogenesis, and neuroplasticity. Dysregulated epigenetic programming has been implicated in the aetiology of several neurodevelopmental disorders such as Tatton-Brown-Rahman syndrome. Accordingly, there is great interest in determining how maternal nutrient availability in pregnancy might affect the epigenetic status of offspring, and how such influences may present phenotypically. In recent years, a number of epigenetic enzymes that are active during embryonic development have been found to require vitamin C as a cofactor. These enzymes include the ten-eleven translocation methylcytosine dioxygenases (TETs) and the Jumonji C domain-containing histone lysine demethylases that catalyse the oxidative removal of methyl groups on cytosines and histone lysine residues, respectively. These enzymes are integral to epigenetic regulation and have fundamental roles in cellular differentiation, the maintenance of pluripotency and development. The dependence of these enzymes on vitamin C for optimal catalytic activity illustrates a potentially critical contribution of the nutrient during mammalian development. These insights also highlight a potential risk associated with vitamin C insufficiency during pregnancy. The link between vitamin C insufficiency and development is particularly apparent in the context of neurodevelopment and high vitamin C concentrations in the brain are indicative of important functional requirements in this organ. Accordingly, this review considers the evidence for the potential impact of maternal vitamin C status on neurodevelopmental epigenetics.
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Clark, Daniel F., Rachael Schmelz, Nicole Rogers, Nuri E. Smith, and Kimberly R. Shorter. "Acute high folic acid treatment in SH-SY5Y cells with and without MTHFR function leads to gene expression changes in epigenetic modifying enzymes, changes in epigenetic marks, and changes in dendritic spine densities." PLOS ONE 16, no. 1 (January 7, 2021): e0245005. http://dx.doi.org/10.1371/journal.pone.0245005.
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Epigenetics are known to be involved in various disorders, including neurobiological disorders like autism. Dietary factors such as folic acid can affect epigenetic marks using methylenetetrahydrofolate reductase (MTHFR) to metabolize folic acid to a one-carbon methyl group. As MTHFR mutations are frequent, it is curious as to whether excess folic acid, with or without functioning MTHFR, could affect gene expression, epigenetics, and neuromorphology. Here, we investigated gene expression and activity of epigenetic modifying enzymes, genome-wide DNA methylation, histone 3 modifications, and dendritic spine densities in SH-SY5Y cells with or without a knockdown of MTHFR and with or without an excess of folic acid. We found alterations to gene expression of epigenetic modifying enzymes, including those associated with disorders like autism. Grouping the epigenetic modifying enzymes by function indicated that gene expression was widely affected for genes that code for enzymes affecting DNA methylation, histone acetylation, histone methylation, histone phosphorylation, and histone ubiquitination when excess folic acid treatment occurred with or without the knockdown of MTHFR. MTHFR was significantly reduced upon excess folic acid treatment whether MTHFR was knocked-down or not. Further, methyl-CpG binding protein 2 expression was significantly decreased with excess folic acid treatment with and without proper MTHFR expression. Global DNA methylation decreased due to the knockdown alone while global hydroxymethylated DNA increased due to the knockdown alone. TET2 expression significantly increased with the MTHFR knockdown alone. Excess folic acid alone induced a decrease in TET3 expression. Excess folic acid induced an increase in dendritic spines without the MTHFR knockdown, but folic acid induced a decrease in dendritic spines when MTHFR was knocked-down. The knockdown alone also increased the dendritic spines significantly. Histone 3 acetylation at lysine 18 was significantly increased when excess folic acid was applied to cells with the MTHFR knockdown, as was histone 3 phosphorylation at serine 10. Broadly, our results indicate that excess folic acid, even with functioning MTHFR, could have detrimental effects on cells.
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Skalnik, David G. "The epigenetic regulator Cfp1." BioMolecular Concepts 1, no. 5-6 (December 1, 2010): 325–34. http://dx.doi.org/10.1515/bmc.2010.031.
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AbstractNumerous epigenetic modifications have been identified and correlated with transcriptionally active euchromatin or repressed heterochromatin and many enzymes responsible for the addition and removal of these marks have been characterized. However, less is known regarding how these enzymes are regulated and targeted to appropriate genomic locations. Mammalian CXXC finger protein 1 is an epigenetic regulator that was originally identified as a protein that binds specifically to any DNA sequence containing an unmethylated CpG dinucleotide. Mouse embryos lacking CXXC finger protein 1 die prior to gastrulation, and embryonic stem cells lacking CXXC finger protein 1 are viable but are unable to achieve cellular differentiation and lineage commitment. CXXC finger protein 1 is a regulator of both cytosine and histone methylation. It physically interacts with DNA methyltransferase 1 and facilitates maintenance cytosine methylation. Rescue studies reveal that CXXC finger protein 1 contains redundant functional domains that are sufficient to support cellular differentiation and proper levels of cytosine methylation. CXXC finger protein 1 is also a component of the Setd1 histone H3-Lys4 methyltransferase complexes and functions to target these enzymes to unmethylated CpG islands. Depletion of CXXC finger protein 1 leads to loss of histone H3-Lys4 tri-methylation at CpG islands and inappropriate drifting of this euchromatin mark into areas of hetero-chromatin. Thus, one function of CXXC finger protein 1 is to serve as an effector protein that interprets cytosine methylation patterns and facilitates crosstalk with histone-modifying enzymes.
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Liu, Yu’e, Chao Chen, Xinye Wang, Yihong Sun, Jin Zhang, Juxiang Chen, and Yufeng Shi. "An Epigenetic Role of Mitochondria in Cancer." Cells 11, no. 16 (August 13, 2022): 2518. http://dx.doi.org/10.3390/cells11162518.
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Mitochondria are not only the main energy supplier but are also the cell metabolic center regulating multiple key metaborates that play pivotal roles in epigenetics regulation. These metabolites include acetyl-CoA, α-ketoglutarate (α-KG), S-adenosyl methionine (SAM), NAD+, and O-linked beta-N-acetylglucosamine (O-GlcNAc), which are the main substrates for DNA methylation and histone post-translation modifications, essential for gene transcriptional regulation and cell fate determination. Tumorigenesis is attributed to many factors, including gene mutations and tumor microenvironment. Mitochondria and epigenetics play essential roles in tumor initiation, evolution, metastasis, and recurrence. Targeting mitochondrial metabolism and epigenetics are promising therapeutic strategies for tumor treatment. In this review, we summarize the roles of mitochondria in key metabolites required for epigenetics modification and in cell fate regulation and discuss the current strategy in cancer therapies via targeting epigenetic modifiers and related enzymes in metabolic regulation. This review is an important contribution to the understanding of the current metabolic-epigenetic-tumorigenesis concept.
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Symeonidis, Argiris, Theodora Chatzilygeroudi, Vasiliki Chondrou, and Argyro Sgourou. "Contingent Synergistic Interactions between Non-Coding RNAs and DNA-Modifying Enzymes in Myelodysplastic Syndromes." International Journal of Molecular Sciences 23, no. 24 (December 16, 2022): 16069. http://dx.doi.org/10.3390/ijms232416069.
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Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders with maturation and differentiation defects exhibiting morphological dysplasia in one or more hematopoietic cell lineages. They are associated with peripheral blood cytopenias and by increased risk for progression into acute myelogenous leukemia. Among their multifactorial pathogenesis, age-related epigenetic instability and the error-rate DNA methylation maintenance have been recognized as critical factors for both the initial steps of their pathogenesis and for disease progression. Although lower-risk MDS is associated with an inflammatory bone marrow microenvironment, higher-risk disease is delineated by immunosuppression and clonal expansion. “Epigenetics” is a multidimensional level of gene regulation that determines the specific gene networks expressed in tissues under physiological conditions and guides appropriate chromatin rearrangements upon influence of environmental stimulation. Regulation of this level consists of biochemical modifications in amino acid residues of the histone proteins’ N-terminal tails and their concomitant effects on chromatin structure, DNA methylation patterns in CpG dinucleotides and the tissue-specific non-coding RNAs repertoire, which are directed against various gene targets. The role of epigenetic modifications is widely recognized as pivotal both in gene expression control and differential molecular response to drug therapies in humans. Insights to the potential of synergistic cooperations of epigenetic mechanisms provide new avenues for treatment development to comfort human diseases with a known epigenetic shift, such as MDS. Hypomethylating agents (HMAs), such as epigenetic modulating drugs, have been widely used in the past years as first line treatment for elderly higher-risk MDS patients; however, just half of them respond to therapy and are benefited. Rational outcome predictors following epigenetic therapy in MDS and biomarkers associated with disease relapse are of high importance to improve our efforts in developing patient-tailored clinical approaches.
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Consalvi, Silvia, Martina Sandoná, and Valentina Saccone. "Epigenetic Reprogramming of Muscle Progenitors: Inspiration for Clinical Therapies." Stem Cells International 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/6093601.
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In the context of regenerative medicine, based on the potential of stem cells to restore diseased tissues, epigenetics is becoming a pivotal area of interest. Therapeutic interventions that promote tissue and organ regeneration have as primary objective the selective control of gene expression in adult stem cells. This requires a deep understanding of the epigenetic mechanisms controlling transcriptional programs in tissue progenitors. This review attempts to elucidate the principle epigenetic regulations responsible of stem cells differentiation. In particular we focus on the current understanding of the epigenetic networks that regulate differentiation of muscle progenitors by the concerted action of chromatin-modifying enzymes and noncoding RNAs. The novel exciting role of exosome-bound microRNA in mediating epigenetic information transfer is also discussed. Finally we show an overview of the epigenetic strategies and therapies that aim to potentiate muscle regeneration and counteract the progression of Duchenne Muscular Dystrophy (DMD).
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Crispo, Fabiana, Michele Pietrafesa, Valentina Condelli, Francesca Maddalena, Giuseppina Bruno, Annamaria Piscazzi, Alessandro Sgambato, Franca Esposito, and Matteo Landriscina. "IDH1 Targeting as a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment—Current State and Future Perspectives." Molecules 25, no. 16 (August 18, 2020): 3754. http://dx.doi.org/10.3390/molecules25163754.
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Cholangiocarcinoma is a primary malignancy of the biliary tract characterized by late and unspecific symptoms, unfavorable prognosis, and few treatment options. The advent of next-generation sequencing has revealed potential targetable or actionable molecular alterations in biliary tumors. Among several identified genetic alterations, the IDH1 mutation is arousing interest due to its role in epigenetic and metabolic remodeling. Indeed, some IDH1 point mutations induce widespread epigenetic alterations by means of a gain-of-function of the enzyme, which becomes able to produce the oncometabolite 2-hydroxyglutarate, with inhibitory activity on α-ketoglutarate-dependent enzymes, such as DNA and histone demethylases. Thus, its accumulation produces changes in the expression of several key genes involved in cell differentiation and survival. At present, small-molecule inhibitors of IDH1 mutated enzyme are under investigation in preclinical and clinical phases as promising innovative treatments for IDH1-mutated intrahepatic cholangiocarcinomas. This review examines the molecular rationale and the results of preclinical and early-phase studies on novel pharmacological agents targeting mutant IDH1 in cholangiocarcinoma patients. Contextually, it will offer a starting point for discussion on combined therapies with metabolic and epigenetic drugs, to provide molecular support to target the interplay between metabolism and epigenetics, two hallmarks of cancer onset and progression.
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Blanquart, Christophe, Camille Linot, Pierre-François Cartron, Daniela Tomaselli, Antonello Mai, and Philippe Bertrand. "Epigenetic Metalloenzymes." Current Medicinal Chemistry 26, no. 15 (July 25, 2019): 2748–85. http://dx.doi.org/10.2174/0929867325666180706105903.
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Epigenetics controls the expression of genes and is responsible for cellular phenotypes. The fundamental basis of these mechanisms involves in part the post-translational modifications (PTMs) of DNA and proteins, in particular, the nuclear histones. DNA can be methylated or demethylated on cytosine. Histones are marked by several modifications including acetylation and/or methylation, and of particular importance are the covalent modifications of lysine. There exists a balance between addition and removal of these PTMs, leading to three groups of enzymes involved in these processes: the writers adding marks, the erasers removing them, and the readers able to detect these marks and participating in the recruitment of transcription factors. The stimulation or the repression in the expression of genes is thus the result of a subtle equilibrium between all the possibilities coming from the combinations of these PTMs. Indeed, these mechanisms can be deregulated and then participate in the appearance, development and maintenance of various human diseases, including cancers, neurological and metabolic disorders. Some of the key players in epigenetics are metalloenzymes, belonging mostly to the group of erasers: the zinc-dependent histone deacetylases (HDACs), the iron-dependent lysine demethylases of the Jumonji family (JMJ or KDM) and for DNA the iron-dependent ten-eleven-translocation enzymes (TET) responsible for the oxidation of methylcytosine prior to the demethylation of DNA. This review presents these metalloenzymes, their importance in human disease and their inhibitors.
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Kolarz, Bogdan, and Maria Majdan. "Epigenetic determinants in rheumatoid arthritis: the influence of DNA methylation and histone modifications." Postępy Higieny i Medycyny Doświadczalnej 71 (December 22, 2017): 0. http://dx.doi.org/10.5604/01.3001.0010.7478.
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Epigenetics is a field of science which describes external and environmental modifications to DNA without altering their primary sequences of nucleotides. Contrary to genetic changes, epigenetic modifications are reversible. The epigenetic changes appear as a result of the influence of external factors, such as diet or stress. Epigenetic mechanisms alter the accessibility of DNA by methylation of DNA or post-translational modifications of histones (acetylation, methylation, phosphorylation, ubiquitinqation). The extent of DNA methylation depends on the balance between DNA methyltransferases and demethylases. The main histone modifications are stimulated by K-acetyltransferases, histone deacetylases, K-metyltransferases and K-demethylases. There is proof that environmental modifications of this enzymes regulate immunological processes including autoimmunity in rheumatoid arthritis (RA). In this work we present epigenetic mechanisms involved in RA pathogenesis and a range of research presenting the possible impact of its modification in RA patients.
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Huang, Yi, Laurence J. Marton, Patrick M. Woster, and Robert A. Casero. "Polyamine analogues targeting epigenetic gene regulation." Essays in Biochemistry 46 (October 30, 2009): 95–110. http://dx.doi.org/10.1042/bse0460007.
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Over the past three decades the metabolism and functions of the polyamines have been actively pursued as targets for antineoplastic therapy. Interactions between cationic polyamines and negatively charged nucleic acids play a pivotal role in DNA stabilization and RNA processing that may affect gene expression, translation and protein activity. Our growing understanding of the unique roles that the polyamines play in chromatin regulation, and the discovery of novel proteins homologous with specific regulatory enzymes in polyamine metabolism, have led to our interest in exploring chromatin remodelling enzymes as potential therapeutic targets for specific polyamine analogues. One of our initial efforts focused on utilizing the strong affinity that the polyamines have for chromatin to create a backbone structure, which could be combined with active-site-directed inhibitor moieties of HDACs (histone deacetylases). Specific PAHAs (polyaminohydroxamic acids) and PABAs (polyaminobenzamides) polyamine analogues have demonstrated potent inhibition of the HDACs, re-expression of p21 and significant inhibition of tumour growth. A second means of targeting the chromatin-remodelling enzymes with polyamine analogues was facilitated by the recent identification of flavin-dependent LSD1 (lysine-specific demethylase 1). The existence of this enzyme demonstrated that histone lysine methylation is a dynamic process similar to other histone post-translational modifications. LSD1 specifically catalyses demethylation of mono- and di-methyl Lys4 of histone 3, key positive chromatin marks associated with transcriptional activation. Structural and catalytic similarities between LSD1 and polyamine oxidases facilitated the identification of biguanide, bisguanidine and oligoamine polyamine analogues that are potent inhibitors of LSD1. Cellular inhibition of LSD1 by these unique compounds led to the re-activation of multiple epigenetically silenced genes important in tumorigenesis. The use of these novel polyamine-based HDAC or LSD1 inhibitors represents a highly promising and novel approach to cancer prevention and therapy.
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Wjst, Matthias, Irene Heimbeck, David Kutschke, and Katrin Pukelsheim. "Epigenetic regulation of vitamin D converting enzymes." Journal of Steroid Biochemistry and Molecular Biology 121, no. 1-2 (July 2010): 80–83. http://dx.doi.org/10.1016/j.jsbmb.2010.03.056.
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Lu, Duo. "Epigenetic modification enzymes: catalytic mechanisms and inhibitors." Acta Pharmaceutica Sinica B 3, no. 3 (May 2013): 141–49. http://dx.doi.org/10.1016/j.apsb.2013.04.007.
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Sibuh, Belay Zeleke, Sameer Quazi, Hrithika Panday, Ritika Parashar, Niraj Kumar Jha, Runjhun Mathur, Saurabh Kumar Jha, Pankaj Taneja, and Abhimanyu Kumar Jha. "The Emerging Role of Epigenetics in Metabolism and Endocrinology." Biology 12, no. 2 (February 6, 2023): 256. http://dx.doi.org/10.3390/biology12020256.
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Each cell in a multicellular organism has its own phenotype despite sharing the same genome. Epigenetics is a somatic, heritable pattern of gene expression or cellular phenotype mediated by structural changes in chromatin that occur without altering the DNA sequence. Epigenetic modification is an important factor in determining the level and timing of gene expression in response to endogenous and exogenous stimuli. There is also growing evidence concerning the interaction between epigenetics and metabolism. Accordingly, several enzymes that consume vital metabolites as substrates or cofactors are used during the catalysis of epigenetic modification. Therefore, altered metabolism might lead to diseases and pathogenesis, including endocrine disorders and cancer. In addition, it has been demonstrated that epigenetic modification influences the endocrine system and immune response-related pathways. In this regard, epigenetic modification may impact the levels of hormones that are important in regulating growth, development, reproduction, energy balance, and metabolism. Altering the function of the endocrine system has negative health consequences. Furthermore, endocrine disruptors (EDC) have a significant impact on the endocrine system, causing the abnormal functioning of hormones and their receptors, resulting in various diseases and disorders. Overall, this review focuses on the impact of epigenetics on the endocrine system and its interaction with metabolism.
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Bridgeman, Stephanie, Wendy Northrop, Gaewyn Ellison, Thiru Sabapathy, Phillip E. Melton, Philip Newsholme, and Cyril D. S. Mamotte. "Statins Do Not Directly Inhibit the Activity of Major Epigenetic Modifying Enzymes." Cancers 11, no. 4 (April 10, 2019): 516. http://dx.doi.org/10.3390/cancers11040516.
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The potential anticancer effects of statins—a widely used class of cholesterol lowering drugs—has generated significant interest, as has the use of epigenetic modifying drugs such as HDAC and DNMT inhibitors. We set out to investigate the effect of statin drugs on epigenetic modifications in multiple cell lines, including hepatocellular carcinoma, breast carcinoma, leukemic macrophages, cervical adenocarcinoma, and insulin-secreting cells, as well as liver extracts from statin-treated C57B1/6J mice. Cells or cell extracts were treated with statins and with established epigenetic modulators, and HDAC, HAT, and DNMT activities were quantified. We also examined histone acetylation by immunoblotting. Statins altered neither HDAC nor HAT activity. Accordingly, acetylation of histones H3 and H4 was unchanged with statin treatment. However, statins tended to increase DNMT activity. These results indicate that direct inhibition of the major classes of epigenetic modifying enzymes, as previously reported elsewhere, is unlikely to contribute to any anticancer effects of statins. This study concerned global effects on epigenetic enzyme activities and histone acetylation; whether statins influence epigenetic modifications in certain genomic regions, cannot be ruled out and remains to be investigated.
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Park, Lara K., Simonetta Friso, and Sang-Woon Choi. "Nutritional influences on epigenetics and age-related disease." Proceedings of the Nutrition Society 71, no. 1 (November 4, 2011): 75–83. http://dx.doi.org/10.1017/s0029665111003302.
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Nutritional epigenetics has emerged as a novel mechanism underlying gene–diet interactions, further elucidating the modulatory role of nutrition in aging and age-related disease development. Epigenetics is defined as a heritable modification to the DNA that regulates chromosome architecture and modulates gene expression without changes in the underlying bp sequence, ultimately determining phenotype from genotype. DNA methylation and post-translational histone modifications are classical levels of epigenetic regulation. Epigenetic phenomena are critical from embryonic development through the aging process, with aberrations in epigenetic patterns emerging as aetiological mechanisms in many age-related diseases such as cancer, CVD and neurodegenerative disorders. Nutrients can act as the source of epigenetic modifications and can regulate the placement of these modifications. Nutrients involved in one-carbon metabolism, namely folate, vitamin B12, vitamin B6, riboflavin, methionine, choline and betaine, are involved in DNA methylation by regulating levels of the universal methyl donor S-adenosylmethionine and methyltransferase inhibitor S-adenosylhomocysteine. Other nutrients and bioactive food components such as retinoic acid, resveratrol, curcumin, sulforaphane and tea polyphenols can modulate epigenetic patterns by altering the levels of S-adenosylmethionine and S-adenosylhomocysteine or directing the enzymes that catalyse DNA methylation and histone modifications. Aging and age-related diseases are associated with profound changes in epigenetic patterns, though it is not yet known whether these changes are programmatic or stochastic in nature. Future work in this field seeks to characterise the epigenetic pattern of healthy aging to ultimately identify nutritional measures to achieve this pattern.
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Illam, Soorya P., Sruthi P. Kandiyil, and Achuthan C. Raghavamenon. "Targeting Histone Onco- Modifications Using Plant-Derived Products." Current Drug Targets 22, no. 11 (August 2, 2021): 1317–31. http://dx.doi.org/10.2174/1389450122666210118150716.
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The regulatory mechanisms lying over the genome that determines the differential expression of genes are termed epigenetic mechanisms. DNA methylation, acetylation, and phosphorylation of histone proteins and RNAi are typical examples. These epigenetic modifications are important determinants of normal growth and metabolism; at the same time, aberrant histone modifications play a major role in pathological conditions and are emerging as a new area of research for the last decades. Histone onco-modification is a term introduced by the scientific world to denote histone post-translational modifications that are associated with cancer development and progression. These modifications are likely to act in certain conditions as adaptive mechanisms to environmental and social factors. The enzymes that regulate DNA methylation as well as histone modifications are thus become a target for cancer therapy and chemoprevention. Since oxidative stress has been shown to modulate epigenetic changes, and phytocompounds with powerful antioxidant properties have a significant role in disease prevention. Nowadays, “nutri- epigenetics” is becoming an emerging area of research that deals with the influence of dietary compounds in epigenetics. This review aims to discuss the biological efficacy of promising phytocompounds that are able to counteract deleterious epigenetic modifications, especially histone onco- modifications.
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Mora, Yuselin, María Elena Reyes, Louise Zanella, Bárbara Mora, Kurt Buchegger, Carmen Ili, and Priscilla Brebi. "Resistance to platinum-based cancer drugs: a special focus on epigenetic mechanisms." Pharmacogenomics 22, no. 12 (August 2021): 777–90. http://dx.doi.org/10.2217/pgs-2021-0020.
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Chemoresistance is a significant clinical challenge, limiting the drug response in cancer. Several mechanisms associated with drug resistance have been characterized, and the role of epigenetics in generating resistance to platinum-based drugs has been clarified. Epigenetic mechanisms such as DNA methylation, histone modification, long noncoding RNA, and microRNA affect the expression of genes implicated in absorption, distribution, metabolism and excretion (ADME) of drugs, and other non-ADME genes that encode enzymes involved in the processes of cell proliferation, DNA repair, apoptosis and signal transduction key in the development of chemoresistance in cancer, specifically in platinum-based drugs. This review summarizes current discoveries in epigenetic regulation implicated in platinum drug resistance in cancer and the main clinical trials based on epigenetic therapy, evaluating their potential synergy with platinum-based drugs.
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Markouli, Mariam, Dimitrios Strepkos, and Christina Piperi. "Impact of Histone Modifications and Their Therapeutic Targeting in Hematological Malignancies." International Journal of Molecular Sciences 23, no. 21 (November 7, 2022): 13657. http://dx.doi.org/10.3390/ijms232113657.
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Hematologic malignancies are a large and heterogeneous group of neoplasms characterized by complex pathogenetic mechanisms. The abnormal regulation of epigenetic mechanisms and specifically, histone modifications, has been demonstrated to play a central role in hematological cancer pathogenesis and progression. A variety of epigenetic enzymes that affect the state of histones have been detected as deregulated, being either over- or underexpressed, which induces changes in chromatin compaction and, subsequently, affects gene expression. Recent advances in the field of epigenetics have revealed novel therapeutic targets, with many epigenetic drugs being investigated in clinical trials. The present review focuses on the biological impact of histone modifications in the pathogenesis of hematologic malignancies, describing a wide range of therapeutic agents that have been discovered to target these alterations and are currently under investigation in clinical trials.
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Arif, K. M. Taufiqul, Esther K. Elliott, Larisa M. Haupt, and Lyn R. Griffiths. "Regulatory Mechanisms of Epigenetic miRNA Relationships in Human Cancer and Potential as Therapeutic Targets." Cancers 12, no. 10 (October 11, 2020): 2922. http://dx.doi.org/10.3390/cancers12102922.
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Initiation and progression of cancer are under both genetic and epigenetic regulation. Epigenetic modifications including alterations in DNA methylation, RNA and histone modifications can lead to microRNA (miRNA) gene dysregulation and malignant cellular transformation and are hereditary and reversible. miRNAs are small non-coding RNAs which regulate the expression of specific target genes through degradation or inhibition of translation of the target mRNA. miRNAs can target epigenetic modifier enzymes involved in epigenetic modulation, establishing a trilateral regulatory “epi–miR–epi” feedback circuit. The intricate association between miRNAs and the epigenetic architecture is an important feature through which to monitor gene expression profiles in cancer. This review summarises the involvement of epigenetically regulated miRNAs and miRNA-mediated epigenetic modulations in various cancers. In addition, the application of bioinformatics tools to study these networks and the use of therapeutic miRNAs for the treatment of cancer are also reviewed. A comprehensive interpretation of these mechanisms and the interwoven bond between miRNAs and epigenetics is crucial for understanding how the human epigenome is maintained, how aberrant miRNA expression can contribute to tumorigenesis and how knowledge of these factors can be translated into diagnostic and therapeutic tool development.
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Kowluru, Renu A., Julia M. Santos, and Manish Mishra. "Epigenetic Modifications and Diabetic Retinopathy." BioMed Research International 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/635284.
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Diabetic retinopathy remains one of the most debilitating chronic complications, but despite extensive research in the field, the exact mechanism(s) responsible for how retina is damaged in diabetes remains ambiguous. Many metabolic pathways have been implicated in its development, and genes associated with these pathways are altered. Diabetic environment also facilitates epigenetics modifications, which can alter the gene expression without permanent changes in DNA sequence. The role of epigenetics in diabetic retinopathy is now an emerging area, and recent work has shown that genes encoding mitochondrial superoxide dismutase (Sod2) and matrix metalloproteinase-9 (MMP-9) are epigenetically modified, activates of epigenetic modification enzymes, histone lysine demethylase 1 (LSD1), and DNA methyltransferase are increased, and the micro RNAs responsible for regulating nuclear transcriptional factor and VEGF are upregulated. With the growing evidence of epigenetic modifications in diabetic retinopathy, better understanding of these modifications has potential to identify novel targets to inhibit this devastating disease. Fortunately, the inhibitors and mimics targeted towards histone modification, DNA methylation, and miRNAs are now being tried for cancer and other chronic diseases, and better understanding of the role of epigenetics in diabetic retinopathy will open the door for their possible use in combating this blinding disease.
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Abdulsalam, Mustapha, Fatima Umar Hamza, Fatima Abubakar Saddeeq, Hafsa Hamisu Ibrahim, Hafsa Ahmad Isa Dutse, and Aisha Mustapha Falaki. "Unveiling the Molecular Symphony: Exploring Mechanisms, Diversity and Applications of Restriction Enzymes in Biology." International Journal of Applied and Scientific Research 2, no. 3 (March 30, 2024): 325–42. http://dx.doi.org/10.59890/ijasr.v2i3.1554.
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This research delves into the multifaceted role of restriction enzymes in molecular biology, examining their historical evolution, intricate mechanisms, and diverse applications. It aims to comprehensively understand their versatility and integration with modern technologies like CRISPR-Cas9, particularly in personalized medicine and gene therapy. Addressing a research gap in the synergism of restriction enzymes with CRISPR-Cas9 and their role in epigenetic modifications, qualitative methods critically assess existing literature and propose future research models. Findings highlight the potential for enhancing genome editing precision and exploring epigenetic alterations involving restriction enzymes, shedding light on DNA methylation, histone modification, and gene expression interplay. Recommendations stress incorporating restriction enzymes in epigenetic studies, offering insights into disease research, personalized medicine, and gene therapy precision. This research contributes to the wealth of discoveries in molecular biology, paving the way for future breakthroughs and deeper insights.
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Mohammed, Hero I., Sahar Hassannejad, and Hoshyar S. Ali. "Cancer Prevention by Epigenetic Modulation of Phytochemicals." Pharmacy and Applied Health Sciences 1, no. 2 (December 30, 2022): 27–41. http://dx.doi.org/10.59480/phahs.v1i2.18.
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"Epigenetics," which emphasizes the impact of active dietary agents on the function of epigenetics, has become an exciting new field of study in recent years. Focusing on aberrant epigenetic alterations during earlier carcinogenesis has been considered in cancer chemotherapy research since, unlike genetic mutations, these differences are reversible. Genes that operate as signal transducers, nuclear receptors, cell cycle regulators, and transcription factors, among others, can be silenced by abnormal epigenetic processes such as DNA promoter methylation, histone changes, and post-transcriptional modifications mediated by miRNA. DNA, gene product maintenance, apoptosis-inducing, and ultimately result in carcinogenesis. An analysis of several natural phytochemicals has been performed on food and medicinal plants to recognize potential and develop anticancer agents that cause the minor lesion to normal cells and effectively destroy cancer cells. A study of several natural phytochemicals found in food and medicinal plants was conducted in order to identify potential and develop anticancer agents that cause a minor lesion in normal cells while effectively destroying cancer cells. According to this study, plant phytochemicals may be involved in the targeted epigenetic modulation of miRNAs, DNA methyltransferases, histone altering enzymes, and carcinogenesis.
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Kadayifci, Fatma Zehra, Shasha Zheng, and Yuan-Xiang Pan. "Molecular Mechanisms Underlying the Link between Diet and DNA Methylation." International Journal of Molecular Sciences 19, no. 12 (December 14, 2018): 4055. http://dx.doi.org/10.3390/ijms19124055.
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DNA methylation is a vital modification process in the control of genetic information, which contributes to the epigenetics by regulating gene expression without changing the DNA sequence. Abnormal DNA methylation—both hypomethylation and hypermethylation—has been associated with improper gene expression, leading to several disorders. Two types of risk factors can alter the epigenetic regulation of methylation pathways: genetic factors and modifiable factors. Nutrition is one of the strongest modifiable factors, which plays a direct role in DNA methylation pathways. Large numbers of studies have investigated the effects of nutrition on DNA methylation pathways, but relatively few have focused on the biochemical mechanisms. Understanding the biological mechanisms is essential for clarifying how nutrients function in epigenetics. It is believed that nutrition affects the epigenetic regulations of DNA methylation in several possible epigenetic pathways: mainly, by altering the substrates and cofactors that are necessary for proper DNA methylation; additionally, by changing the activity of enzymes regulating the one-carbon cycle; and, lastly, through there being an epigenetic role in several possible mechanisms related to DNA demethylation activity. The aim of this article is to review the potential underlying biochemical mechanisms that are related to diet modifications in DNA methylation and demethylation.
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Butler, Jill S., and Sharon Y. R. Dent. "The role of chromatin modifiers in normal and malignant hematopoiesis." Blood 121, no. 16 (April 18, 2013): 3076–84. http://dx.doi.org/10.1182/blood-2012-10-451237.
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Abstract Complex developmental processes such as hematopoiesis require a series of precise and coordinated changes in cellular identity to ensure blood homeostasis. Epigenetic mechanisms help drive changes in gene expression that accompany the transition from hematopoietic stem cells to terminally differentiated blood cells. Genome-wide profiling technologies now provide valuable glimpses of epigenetic changes that occur during normal hematopoiesis, and genetic mouse models developed to investigate the in vivo functions of chromatin-modifying enzymes clearly demonstrate significant roles for these enzymes during embryonic and adult hematopoiesis. Here, we will review the basic science aspects of chromatin modifications and the enzymes that add, remove, and interpret these epigenetic marks. This overview will provide a framework for understanding the roles that these molecules play during normal hematopoiesis. Moreover, many chromatin-modifying enzymes are involved in hematologic malignancies, underscoring the importance of establishing and maintaining appropriate chromatin modification patterns to normal hematology.
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Wulansari, Noviana, Yanuar Alan Sulistio, Wahyu Handoko Wibowo Darsono, Chang-Hoon Kim, and Sang-Hun Lee. "LIF maintains mouse embryonic stem cells pluripotency by modulating TET1 and JMJD2 activity in a JAK2-dependent manner." Stem Cells 39, no. 6 (February 11, 2021): 750–60. http://dx.doi.org/10.1002/stem.3345.
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Abstract The LIF-JAK2-STAT3 pathway is the central signal transducer that maintains undifferentiated mouse embryonic stem cells (mESCs), which is achieved by the recruitment of activated STAT3 to the master pluripotency genes and activation of the gene transcriptions. It remains unclear, however, how the epigenetic status required for the master gene transcriptions is built into LIF-treated mESC cultures. In this study, Jak2, but not Stat3, in the LIF canonical pathway, establishes an open epigenetic status in the pluripotency gene promoter regions. Upon LIF activation, cytosolic JAK2 was translocalized into the nucleus of mESCs, and reduced DNA methylation (5mC levels) along with increasing DNA hydroxymethylation (5hmC) in the pluripotent gene (Nanog/Pou5f1) promoter regions. In addition, the repressive histone codes H3K9m3/H3K27m3 were reduced by JAK2. Activated JAK2 directly interacted with the core epigenetic enzymes TET1 and JMJD2, modulating its activity and promotes the DNA and histone demethylation, respectively. The JAK2 effects were attained by tyrosine phosphorylation on the epigenetic enzymes. The effects of JAK2 phosphorylation on the enzymes were diverse, but all were merged to the epigenetic signatures associated with open DNA/chromatin structures. Taken together, these results reveal a previously unrecognized epigenetic regulatory role of JAK2 as an important mediator of mESC maintenance.
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Pethő, Gábor, Boglárka Kántás, Ádám Horváth, and Erika Pintér. "The Epigenetics of Neuropathic Pain: A Systematic Update." International Journal of Molecular Sciences 24, no. 24 (December 5, 2023): 17143. http://dx.doi.org/10.3390/ijms242417143.
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Epigenetics deals with alterations to the gene expression that occur without change in the nucleotide sequence in the DNA. Various covalent modifications of the DNA and/or the surrounding histone proteins have been revealed, including DNA methylation, histone acetylation, and methylation, which can either stimulate or inhibit protein expression at the transcriptional level. In the past decade, an exponentially increasing amount of data has been published on the association between epigenetic changes and the pathomechanism of pain, including its most challenging form, neuropathic pain. Epigenetic regulation of the chromatin by writer, reader, and eraser proteins has been revealed for diverse protein targets involved in the pathomechanism of neuropathic pain. They include receptors, ion channels, transporters, enzymes, cytokines, chemokines, growth factors, inflammasome proteins, etc. Most work has been invested in clarifying the epigenetic downregulation of mu opioid receptors and various K+ channels, two types of structures mediating neuronal inhibition. Conversely, epigenetic upregulation has been revealed for glutamate receptors, growth factors, and lymphokines involved in neuronal excitation. All these data cannot only help better understand the development of neuropathic pain but outline epigenetic writers, readers, and erasers whose pharmacological inhibition may represent a novel option in the treatment of pain.