Epigenetic marks in melanoma

Melanoma is a highly heterogeneous cancer that comes in different flavors (lentigo maligna melanoma, superficial spreading melanoma, nodular melanoma, acral lentiginous/mucosal melanoma and other less common subtypes including malignant cellular blue nevus, desmoplastic melanoma, nevoid melanoma, and animal‐type melanoma) and colors (black/bluish or unpigmented). Pathologists have known for many years that melanoma displays notable changes in the nuclear architecture including thick chromatic rims, presence of mitosis, nuclear grooves, and more. It is now evident from other cancers that such changes reflect not only genomic alterations but also non‐genomic changes in both the structure of DNA and the structure of chromatin to which the DNA is bound (nucleosomes). Although aberrant gene expression resulting from DNA methylation has been known for many years, genome alterations resulting from histone modifications became evident in the current decade. In prostate and other cancers, some histone marks have clinical diagnostic and/or prognostic value. Here, we review the current data on epigenetic research in melanoma skin cancers, discuss ways to modify the epigenetic landscape of melanoma for inhibiting its growth, and propose strategies for identifying novel melanoma markers.     

Silencing of transgene expression in mammalian cells by DNA methylation and histone modifications in gene therapy perspective

DNA methylation and histone modifications are vital in maintaining genomic stability and modulating cellular functions in mammalian cells. These two epigenetic modifications are the most common gene regulatory systems known to spatially control gene expression. Transgene silencing by these two mechanisms is a major challenge to achieving effective gene therapy for many genetic conditions. The implications of transgene silencing caused by epigenetic modifications have been extensively studied and reported in numerous gene delivery studies. This review highlights instances of transgene silencing by DNA methylation and histone modification with specific focus on the role of these two epigenetic effects on the repression of transgene expression in mammalian cells from integrative and non-integrative based gene delivery systems in the context of gene therapy. It also discusses the prospects of achieving an effective and sustained transgene expression for future gene therapy applications.     

Epigenetic regulation: methylation of histone and non-histone proteins

Histone methylation is believed to play important roles in epigenetic memory in various biological processes. However, questions like whether the methylation marks themselves are faithfully transmitted into daughter cells and through what mechanisms are currently under active investigation. Previously, methylation was considered to be irreversible, but the recent discovery of histone lysine demethylases revealed a dynamic nature of histone methylation regulation on four of the main sites of methylation on histone H3 and H4 tails (H3K4, H3K9, H3K27 and H3K36). Even so, it is still unclear whether demethylases specific for the remaining two sites, H3K79 and H4K20, exist. Furthermore, besides histone proteins, the lysine methylation and demethylation also occur on non-histone proteins, which are probably subjected to similar regulation as histones. This review discusses recent progresses in protein lysine methylation regulation focusing on the above topics, while referring readers to a number of recent reviews for the biochemistry and biology of these enzymes     

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。     

表观遗传修饰介导的植物胁迫记忆

植物因其固着生长的方式, 已经进化出各类特殊的机制来适应多变的外界环境。为提高自身的存活率, 植物进化出一类胁迫记忆机制, 以适应环境和保护自己。表观遗传修饰不仅能调控植物的正常生长发育, 而且参与植物对各种非生物或生物胁迫的响应。近年的研究表明, 表观遗传修饰在植物胁迫记忆调控中也发挥重要作用。例如, DNA甲基化、组蛋白甲基化及乙酰化等表观遗传修饰参与并维持特定的胁迫记忆。该文主要对表观遗传修饰介导的植物胁迫记忆最新进展进行综述, 并展望未来的重点和热点研究方向。     

黑色素瘤发生发展中的表观遗传学调控

人恶性黑色素瘤(malignant melanoma)是近年来高发病率和高死亡率的肿瘤之一.目前尚缺乏有效的治疗方法.而表观遗传如DNA甲基化(DNA methylation)、组蛋白修饰(histonemodification)、染色质重塑(chromatin remodeling)及RNA干扰(RNA interference,RNAi)等改变在人黑色素瘤的发生、发展和转移中有重要作用.阐明黑色素瘤发生发展的表观遗传学机制已引起了学者的普遍关注.本文综述了人类黑色素瘤发生发展中所特异的表观遗传改变:CpG岛的异常甲基化修饰、组蛋白甲基化和乙酰化修饰、染色质重塑以及microRNA在黑色素瘤发生和转移中的作用,并对应用表观遗传修饰治疗人类黑色素瘤进行了探讨.     

表观遗传修饰介导的植物胁迫记忆

植物因其固着生长的方式, 已经进化出各类特殊的机制来适应多变的外界环境。为提高自身的存活率, 植物进化出一类胁迫记忆机制, 以适应环境和保护自己。表观遗传修饰不仅能调控植物的正常生长发育, 而且参与植物对各种非生物或生物胁迫的响应。近年的研究表明, 表观遗传修饰在植物胁迫记忆调控中也发挥重要作用。例如, DNA甲基化、组蛋白甲基化及乙酰化等表观遗传修饰参与并维持特定的胁迫记忆。该文主要对表观遗传修饰介导的植物胁迫记忆最新进展进行综述, 并展望未来的重点和热点研究方向。     

细胞自噬发生的表观遗传调节

细胞自噬是一种进化上保守的, 通过吞噬降解自身大分子物质或细胞器来维持细胞生存的活动。自噬与多种生命活动息息相关, 其功能的紊乱往往会导致肿瘤发生、神经退行性疾病、微生物感染等疾病。研究表明, 表观遗传修饰可以调控细胞自噬的发生, 并在细胞自噬的生物学功能调节过程中发挥重要作用, 但具体调控机制尚需进一步探究。文章综述了细胞自噬发生过程中存在的表观遗传效应, 包括组蛋白乙酰化对细胞自噬激活或抑制的负反馈调控, 通过DNA甲基化调节自噬相关基因活性来影响细胞自噬的发生, miRNA通过靶向调节自噬相关基因表达来影响组蛋白修饰, 从而调控细胞自噬的发生及作用过程等, 旨在为人们进一步研究细胞自噬发生过程中的表观遗传修饰及其机制提供信息依据。     

Np95 interacts with de novo DNA methyltransferases,Dnmt3a and Dnmt3b,and mediates epigenetic silencing of the viral CMV promoter in embryonic stem cells

Recent studies have indicated that nuclear protein of 95 kDa (Np95) is essential for maintaining genomic methylation by recruiting DNA methyltransferase (Dnmt) 1 to hemi‐methylated sites. Here, we show that Np95 interacts more strongly with regulatory domains of the de novo methyltransferases Dnmt3a and Dnmt3b. To investigate possible functions, we developed an epigenetic silencing assay using fluorescent reporters in embryonic stem cells (ESCs). Interestingly, silencing of the cytomegalovirus promoter in ESCs preceded DNA methylation and was strictly dependent on the presence of either Np95, histone H3 methyltransferase G9a or Dnmt3a and Dnmt3b. Our results indicate a regulatory role for Np95, Dnmt3a and Dnmt3b in mediating epigenetic silencing through histone modification followed by DNA methylation.     

UBE3A-mediated regulation of imprinted genes and epigenome-wide marks in human neurons

The dysregulation of genes in neurodevelopmental disorders that lead to social and cognitive phenotypes is a complex, multilayered process involving both genetics and epigenetics. Parent-of-origin effects of deletion and duplication of the 15q11-q13 locus leading to Angelman, Prader-Willi, and Dup15q syndromes are due to imprinted genes, including UBE3A, which is maternally expressed exclusively in neurons. UBE3A encodes a ubiquitin E3 ligase protein with multiple downstream targets, including RING1B, which in turn monoubiquitinates histone variant H2A.Z. To understand the impact of neuronal UBE3A levels on epigenome-wide marks of DNA methylation, histone variant H2A.Z positioning, active H3K4me3 promoter marks, and gene expression, we took a multi-layered genomics approach. We performed an siRNA knockdown of UBE3A in two human neuroblastoma cell lines, including parental SH-SY5Y and the SH(15M) model of Dup15q. Genes differentially methylated across cells with differing UBE3A levels were enriched for functions in gene regulation, DNA binding, and brain morphology. Importantly, we found that altering UBE3A levels had a profound epigenetic effect on the methylation levels of up to half of known imprinted genes. Genes with differential H2A.Z peaks in SH(15M) compared to SH-SY5Y were enriched for ubiquitin and protease functions and associated with autism, hypoactivity, and energy expenditure. Together, these results support a genome-wide epigenetic consequence of altered UBE3A levels in neurons and suggest that UBE3A regulates an imprinted gene network involving DNA methylation patterning and H2A.Z deposition.     

Epigenetic Regulations in Mammalian Cells: Roles and Profiling Techniques

The genome is almost identical in all the cells of the body. However, the functions and morphologies of each cell are different, and the factors that determine them are the genes and proteins expressed in the cells. Over the past decades, studies on epigenetic information, such as DNA methylation, histone modifications, chromatin accessibility, and chromatin conformation have shown that these properties play a fundamental role in gene regulation. Furthermore, various diseases such as cancer have been found to be associated with epigenetic mechanisms. In this study, we summarized the biological properties of epigenetics and single-cell epigenomic profiling techniques, and discussed future challenges in the field of epigenetics.     

非生物胁迫下植物表观遗传变异的研究进展

植物在整个生命过程中固着生长,不能主动躲避外界不良环境的危害,需要通过自身的防御机制来抵御和适应外界胁迫,而表观遗传修饰在调控植物应对不良环境胁迫中起重要作用。该文从DNA甲基化、组蛋白修饰、染色质重塑和非编码RNA等方面进行了综述,主要阐述了近年来国内外有关非生物胁迫下植物的表观遗传变化,以期为利用表观遗传变异提高植物的抗胁迫能力提供参考。     

Conservation of Aging and Cancer Epigenetic Signatures across Human and Mouse

Aging and cancer are two interrelated processes, with aging being a major risk factor for the development of cancer. Parallel epigenetic alterations have been described for both, although differences, especially within the DNA hypomethylation scenario, have also been recently reported. Although many of these observations arise from the use of mouse models, there is a lack of systematic comparisons of human and mouse epigenetic patterns in the context of disease. However, such comparisons are significant as they allow to establish the extent to which some of the observed similarities or differences arise from pre-existing species-specific epigenetic traits. Here, we have used reduced representation bisulfite sequencing to profile the brain methylomes of young and old, tumoral and nontumoral brain samples from human and mouse. We first characterized the baseline epigenomic patterns of the species and subsequently focused on the DNA methylation alterations associated with cancer and aging. Next, we described the functional genomic and epigenomic context associated with the alterations, and finally, we integrated our data to study interspecies DNA methylation levels at orthologous CpG sites. Globally, we found considerable differences between the characteristics of DNA methylation alterations in cancer and aging in both species. Moreover, we describe robust evidence for the conservation of the specific cancer and aging epigenomic signatures in human and mouse. Our observations point toward the preservation of the functional consequences of these alterations at multiple levels of genomic regulation. Finally, our analyses reveal a role for the genomic context in explaining disease- and species-specific epigenetic traits.     

Changes in soluble proteins in callus cells of hypersensitive tobacco inoculated with tobacco mosaic virus

Summary Protein changes occurred in callus cells of hypersensitive tobacco (Nicotiana tabacum var. Xanthi-nc) 72 hr after inoculation with tobacco mosaic virus and incubation on a minimal growth medium. Two protein bands, serologically related to viral coat protein, were obtained from extracts of infected cells following electrophoresis on 7% and 10% polyacrylamide gels. An additional, slower migrating protein, perhaps due to virus-induced stimulation of a host protein, also was detected. Although local lesions appeared on callus after 40 hr of incubation, four proteins previously reported in lesion-bearing hypersensitive tobacco leaves were not found. The possible significance of this and the usefulness of a callus-TMV system as a tool to study virus-induced protein changes are discussed. Michigan Agricultural Experiment Station Journal Paper No. 7191.