Epigenetic regulation of autophagy in coronavirus disease 2019 (COVID-19)

The coronavirus disease 2019 (COVID-19) pandemic has become the most serious global public health issue in the past two years, requiring effective therapeutic strategies. This viral infection is a contagious disease caused by new coronaviruses (nCoVs), also called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Autophagy, as a highly conserved catabolic recycling process, plays a significant role in the growth and replication of coronaviruses (CoVs). Therefore, there is great interest in understanding the mechanisms that underlie autophagy modulation. The modulation of autophagy is a very complex and multifactorial process, which includes different epigenetic alterations, such as histone modifications and DNA methylation. These mechanisms are also known to be involved in SARS-CoV-2 replication. Thus, molecular understanding of the epigenetic pathways linked with autophagy and COVID-19, could provide novel therapeutic targets for COVID-19 eradication. In this context, the current review highlights the role of epigenetic regulation of autophagy in controlling COVID-19, focusing on the potential therapeutic implications.     

表观遗传学研究进展

表观遗传学是在基因组DNA序列不发生变化的条件下,基因表达发生的改变也是可以遗传的,导致可遗传的表现型变化。表观遗传学主要包括DNA甲基化作用、组蛋白修饰作用、染色质重塑、遗传印记、随机染色体(X)失活及RNA世界等。与表观遗传学相关的疾病主要有肿瘤、心血管病、精神病和自身免疫系统性病等。现就表观遗传学与疾病进行综述。     

表观遗传学及其研究方法

表观遗传学是一门重要的生命学科,主要包括DNA的甲基化、组蛋白修饰以及非编码RNA等内容,其中任何一方面的表观遗传学变化对生物体的生命过程都有重要的影响。近年来随着生命科学的快速发展,表观遗传学越来越受到人们的关注,各种先进科技的应用也使得表观遗传学实验技术得到快速的发展。本文对DNA甲基化、组蛋白修饰及非编码RNA的基本内容及实验方法进行了综述,并对不同的研究方法进行分析,有利于表观遗传学的深入研究。     

Epigenetic regulation in the carcinogenesis of cholangiocarcinoma

Cholangiocarcinoma (CCA) is a malignancy arising from the epithelial cells lining the biliary tract. Despite the existence of variation in incidence and etiology worldwide, its incidence is increasing globally in the past few decades. Surgery is the only curative treatment option for a minority of patients presented with early disease; while moderate effective chemotherapy remains the standard care for patients with locally advanced or metastatic diseases. In this article, we briefly review the molecular alterations that have been described in CCAs focusing on the role of epigenetic modification, including promoter methylation inactivation, histone modification and microRNA, in the carcinogenesis and progression of CCAs. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease.     

表观遗传学与子宫内膜癌的研究进展

长期以来人们一直认为基因突变或缺失参与肿瘤的形成,近年来越来越多证据表明,表观遗传修饰在肿瘤进展中同样具有非常重要的作用。DNA甲基化、组蛋白修饰及microRNA表达调控等表观遗传机制是子宫内膜癌发生、发展的重要原因之一。表观遗传学的研究进展不仅有助于子宫内膜癌的早期诊断,对分子靶向治疗子宫内膜癌亦显示出良好的应用前景。     

表观遗传学与子宫内膜癌的研究进展

长期以来人们一直认为基因突变或缺失参与肿瘤的形成,近年来越来越多证据表明,表观遗传修饰在肿瘤进展中同样具有非常重要的作用。DNA甲基化、组蛋白修饰及micro RNA表达调控等表观遗传机制是子宫内膜癌发生、发展的重要原因之一。表观遗传学的研究进展不仅有助于子宫内膜癌的早期诊断,对分子靶向治疗子宫内膜癌亦显示出良好的应用前景。     

Chromatin regulators of genomic imprinting

Genomic imprinting is an epigenetic phenomenon in which genes are expressed monoallelically in a parent-of-origin-specific manner. Each chromosome is imprinted with its parental identity. Here we will discuss the nature of this imprinting mark. DNA methylation has a well-established central role in imprinting, and the details of DNA methylation dynamics and the mechanisms that target it to imprinted loci are areas of active investigation. However, there is increasing evidence that DNA methylation is not solely responsible for imprinted expression. At the same time, there is growing appreciation for the contributions of post-translational histone modifications to the regulation of imprinting. The integration of our understanding of these two mechanisms is an important goal for the future of the imprinting field. This article is part of a Special Issue entitled: Chromatin and epigenetic regulation of animal development.     

Current advances in epigenetic modification and alteration during mammalian ovarian folliculogenesis

During the growth and development of mammalian ovarian follicles, the activation and deactivation of mass genes are under the synergistic control of diverse modifiers through genetic and epigenetic events. Many factors regulate gene activity and functions through epigenetic modification without altering the DNA sequence, and the common mechanisms may include but are not limited to: DNA methylation, histone modifications (e.g., acetylation, deacetylation, phosphorylation, methylation, and ubiquitination), and RNA-associated silencing of gene expression by noncoding RNA. Over the past decade, substantial progress has been achieved in studies involving the epigenetic alterations during mammalian germ cell development. A number of candidate regulatory factors have been identified. This review focuses on the current available information of epigenetic alterations (e.g., DNA methylation, histone modification, noncoding-RNA-mediated regulation) during mammalian folliculogenesis and recounts when and how epigenetic patterns are differentially established, maintained, or altered in this process. Based on different types of epigenetic regulation, our review follows the temporal progression of events during ovarian folliculogenesis and describes the epigenetic changes and their contributions to germ cell-specific functions at each stage (i.e., primordial folliculogenesis (follicle formation), follicle maturation, and follicular atresia).     

Histone methylation marks play important roles in predicting the methylation status of CpG islands

The methylation status of CpG islands is highly correlated with gene expression. Current methods for computational prediction of DNA methylation only utilize DNA sequence features. In this study, besides 35 DNA sequence features, we added four histone methylation marks to predict the methylation status of CpG islands, and improved the accuracy to 89.94%. Also we applied our model to predict the methylation pattern of all the CpG islands in the human genome, and the results are consistent with the previous reports. Our results imply the important roles of histone methylation marks in affecting the methylation status of CpG islands. H3K4me enriched in the methylation-resistant CpG islands could disrupt the contacts between nucleosomes, unravel chromatin and make DNA sequences accessible. And the established open environment may be a prerequisite for or a consequence of the function implementation of zinc finger proteins that could protect CpG islands from DNA methylation.     

表遗传学研究进展及其应用

表遗传体系包括DNA甲基化、RNA干涉、基因组印迹和组蛋白密码等多方面。它们们在生物体生长发育过程中对基因表达和调控有重要作用,而且与生物体的防御机制和生物遗传信息的传递存在密切联系。表遗传在肿瘤上也有重要应用,表遗传机制的异常通过使癌遗传学途径基因失能与获能、增加基因组的不稳定性和印迹丢失等途径参与肿瘤的形成,同时也启发了对肿瘤防治的研究。就表遗传这一新的分子生物学研究领域的发展及最新研究进展进行了综述。     

Epigenetic changes induced by curcumin and other natural compounds

Epigenetic regulation, which includes changes in DNA methylation, histone modifications, and alteration in microRNA (miRNA) expression without any change in the DNA sequence, constitutes an important mechanism by which dietary components can selectively activate or inactivate gene expression. Curcumin (diferuloylmethane), a component of the golden spice Curcuma longa, commonly known as turmeric, has recently been determined to induce epigenetic changes. This review summarizes current knowledge about the effect of curcumin on the regulation of histone deacetylases, histone acetyltransferases, DNA methyltransferase I, and miRNAs. How these changes lead to modulation of gene expression is also discussed. We also discuss other nutraceuticals which exhibit similar properties. The development of curcumin for clinical use as a regulator of epigenetic changes, however, needs further investigation to determine novel and effective chemopreventive strategies, either alone or in combination with other anticancer agents, for improving cancer treatment.     

Effect of maternal zinc deficiency on offspring health: The epigenetic impact

BackgroundZinc deficiency is associated with adverse effects on maternal health and pregnancy outcomes. These consequences have been reported over the years from zinc supplementation trials and observational studies whereby outcomes of maternal, foetal and infant health were measured. Owing to the importance of zinc in the functions of epigenetic enzymes, pre-clinical studies have shown that its deficiency could disrupt biological activities that involve epigenetic mechanisms in offspring. Thus, this review assessed the link between epigenetics and the effects of maternal zinc deficiency on the offspring’s health in animal studies.MethodsResearch articles were retrieved without date restriction from PubMed, Web of Science, ScienceDirect, and Google Scholar databases, as well as reference lists of relevant articles. The search terms used were “zinc deficiency”, “maternal zinc deficiency”, “epigenetics”, and “offspring.” Six studies met the eligibility criteria and were reviewed.ResultsAll the eligible studies reported maternal zinc deficiency and observed changes in epigenetic markers on the progeny during prenatal and postnatal stages of development. The main epigenetic markers reported were global and gene specific methylation and/ or acetylation. The epigenetic changes led to mortality, disruption in development, and risk of later life diseases.ConclusionMaternal zinc deficiency is associated with epigenetic modifications in offspring, which induce pathologies and increase the risk of later life diseases. More research and insight into the epigenetic mechanisms could spring up new approaches to combat the associated disease conditions.     

Dynamic chromatin modifications characterise the first cell cycle in mouse embryos

On fertilisation, gametes undergo epigenetic reorganisation and re-establish totipotency. Here, we investigate links between chromatin remodelling and asymmetric maintenance of DNA methylation in the early mouse embryo. Using antibodies for lysine specific H3 methylation reveals that the male pronucleus is negative for di- and trimethyl H3-K9 yet the female is positive for these residues. However, the male is positive for monomethyl H3-K9 and H3-K27 and these signals increase during pronuclear maturation. Non-histone chromatin proteins of the Polycomb group are found in the paternal compartment as early as sperm decondensation. However, trimethyl H3-K27 is not observed in the male until the completion of DNA replication. Heterochromatin protein 1 beta (HP1beta) is abundant in the male pronucleus, despite the absence of di- and trimethyl H3-K9, and co-localises with monomethyl H3-K9. Recent evidence identifies monomethyl H3-K9 as the preferred substrate of Suvar39h, the histone methyl transferase (HMT) responsible for heterochromatic H3-K9 trimethylation. The association of HP1beta with monomethyl H3-K9 may assist in preventing further modification of H3-K9. Association of dimethylation but not trimethylation of H3-K9 with DNA methylation, in the female pronucleus, suggests a mechanistically significant link. These differences begin to provide a chromatin based explanation for paternal-specific active DNA demethylation and maternal specific protection in the mouse.     

Epigenetic regulation of autophagy: A key modification in cancer cells and cancer stem cells

Aberrant epigenetic alterations play a decisive role in cancer initiation and propagation via the regulation of key tumor suppressor genes and oncogenes or by modulation of essential signaling pathways. Autophagy is a highly regulated mechanism required for the recycling and degradation of surplus and damaged cytoplasmic constituents in a lysosome dependent manner. In cancer, autophagy has a divergent role. For instance, autophagy elicits tumor promoting functions by facilitating metabolic adaption and plasticity in cancer stem cells (CSCs) and cancer cells. Moreover, autophagy exerts pro-survival mechanisms to these cancerous cells by influencing survival, dormancy, immunosurveillance, invasion, metastasis, and resistance to anti-cancer therapies. In addition, recent studies have demonstrated that various tumor suppressor genes and oncogenes involved in autophagy, are tightly regulated via different epigenetic modifications, such as DNA methylation, histone modifications and non-coding RNAs. The impact of epigenetic regulation of autophagy in cancer cells and CSCs is not well-understood. Therefore, uncovering the complex mechanism of epigenetic regulation of autophagy provides an opportunity to improve and discover novel cancer therapeutics. Subsequently, this would aid in improving clinical outcome for cancer patients. In this review, we provide a comprehensive overview of the existing knowledge available on epigenetic regulation of autophagy and its importance in the maintenance and homeostasis of CSCs and cancer cells.     

An Overview of Epigenetic Assays

A significant portion of ongoing epigenetic research involves the investigation of DNA methylation and chromatin modification patterns seen throughout many biological processes. Over the last few years, epigenetic research has undergone a gradual shift and recent studies have been directed toward a genome-wide assessment. DNA methylation and chromatin modifications are essential components of the regulation of gene activity. DNA methylation effectively down-regulates gene activity by addition of a methyl group to the five-carbon of a cytosine base. Less specifically, modification of the chromatin structure can be carried out by multiple mechanisms leading to either the upregulation or down-regulation of the associated gene. Of the many assays used to assess the effects of epigenetic modifications, chromatin immunoprecipitation (ChIP), which serves to monitor changes in chromatin structure, and bisulfite modification, which tracks changes in DNA methylation, are the two most commonly used techniques. J. T. DeAngelis and W. J. Farrington are contributed equally.     

Epigenetic regulation of extracellular-superoxide dismutase in human monocytes

Extracellular-superoxide dismutase (EC-SOD) is a major SOD isozyme mainly present in the vascular wall and plays an important role in normal redox homeostasis. We previously showed the significant reduction or induction of EC-SOD during human monocytic U937 or THP-1 cell differentiation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), respectively; however, its cell-specific expression and regulation have not been fully elucidated. It has been reported that epigenetic factors, such as DNA methylation and histone modification, are involved in several kinds of gene regulation. In this study, we investigated the involvement of epigenetic factors in EC-SOD expression and determined high levels of DNA methylation within promoter and coding regions of EC-SOD in THP-1 cells compared to those in U937 cells. Moreover, treatment with a DNA methyltransferase inhibitor, 5-azacytidine, significantly induced the expression of EC-SOD in THP-1 cells, indicating the importance of DNA methylation in the suppression of EC-SOD expression; however, the DNA methylation status did not change during THP-1 cell differentiation induced by TPA. On the other hand, we detected histone H3 and H4 acetylation during differentiation. Further, pretreatment with histone acetyltransferase inhibitors, CPTH2 or garcinol, significantly suppressed the TPA-inducible EC-SOD expression. We also determined the epigenetic suppression of EC-SOD in peripheral blood mononuclear cells. Treatment with granulocyte macrophage colony-stimulating factor (GM-CSF)/granulocyte-CSF induced that expression. Overall, these findings provide novel evidence that cell-specific and TPA-inducible EC-SOD expression are regulated by DNA methylation and histone H3 and H4 acetylation in human monocytic cells.     

表观遗传修饰在调控寿命中的作用

表观遗传修饰是生命现象中普遍存在的一类基因调控方式,主要包括DNA甲基化、组蛋白乙酰化和组蛋白甲基化等,通常协同调控基因表达。端粒是位于真核生物染色体末端的保护性结构,在端粒以及亚端粒区域中也存在丰富的表观遗传修饰。随着研究深入,发现表观遗传修饰在调控寿命过程中扮演着重要角色,而揭示衰老的有关机制有助于我们找到延长寿命的方法,具有重大的生物学意义和临床应用前景。