表观遗传学及现代表观遗传生物医药技术的发展北大核心CSCD

表观遗传学和基于表观遗传机制的生物医药技术的研究已经成为后基因组时代生命科学技术领域的重要组成部分。围绕肿瘤、心脑血管疾病、糖尿病及中老年神经退行性疾病等过程中DNA甲基化修饰、组蛋白翻译后修饰及非编码RNA等表观遗传学改变的深入研究,不仅有利于理解相关疾病的分子病理机制,而且,更有助于探寻基于表观遗传机制的有效治疗手段。在阐释表观遗传学修饰机制的基础上,对疾病过程中异常的表观遗传学修饰及相关生物医药技术的研究现状进行了归纳总结。     

表观遗传学及现代表观遗传生物医药技术的发展

表观遗传学和基于表观遗传机制的生物医药技术的研究已经成为后基因组时代生命科学技术领域的重要组成部分。围绕肿瘤、心脑血管疾病、糖尿病及中老年神经退行性疾病等过程中DNA甲基化修饰、组蛋白翻译后修饰及非编码RNA等表观遗传学改变的深入研究,不仅有利于理解相关疾病的分子病理机制,而且,更有助于探寻基于表观遗传机制的有效治疗手段。在阐释表观遗传学修饰机制的基础上,对疾病过程中异常的表观遗传学修饰及相关生物医药技术的研究现状进行了归纳总结。     

表观遗传修饰与肿瘤

肿瘤的形成受遗传学修饰和表观遗传修饰的影响。长期以来人们一直认为基因突变参与肿瘤的形成,近年来越来越多的证据表明,表观遗传修饰在肿瘤进展中同样具有非常重要的作用。表观遗传调控可以影响基因转录活性而不涉及DNA序列的改变。本文介绍了肿瘤发生发展过程中出现的表观遗传修饰异常,以及通过干预表观遗传修饰治疗肿瘤的应用前景。     

鼻咽癌的表观遗传学研究进展

表观遗传学是功能基因组学的重要组成部分,它实际上是研究理化、生物等环境因素以及饮食习惯等对遗传因素的作用,并由这一作用引起DNA序列以外的遗传物质改变.鼻咽癌是我国南方常见恶性肿瘤,具有明显的家族聚集倾向,存在基因组不稳定性,易受理化、生物等环境因素的影响,是多基因遗传性肿瘤.鼻咽癌这种独特病因体系提示:鼻咽癌是研究肿瘤表观遗传修饰的最佳模型之一.主要从DNA甲基化、组蛋白修饰、染色质重构和非编码RNA的调控4方面对鼻咽癌表观遗传学研究进展进行综述并针对性地提出了一些新的建议,目的是为进一步探究鼻咽癌表观遗传学发病机制,更好地全面理解鼻咽癌的病因发病机制网络体系,寻找鼻咽癌高危易感人群的筛查、早期诊断、治疗、预后判断的表观遗传修饰分子标志物开辟新的前景.     

非编码RNA诱导的表观遗传学与肿瘤的发生

ncRNA可以通过多种遗传机理调控DNA的结构、RNA的表达和稳定性以及蛋白质的翻译和功能,最近研究证实小RNA可以通过指导基因组表现修饰DNA甲基化和组蛋白修饰引起癌遗传学途径基因失能与获能,增加基因组不稳定,印记丢失等途径参与肿瘤的发生发展.探索ncRNA对肿瘤细胞中基因的异常表达的影响和作用有助于将癌基因组学与表观遗传学的研究结合起来.为研发防治肿瘤的新方法和新途径提供新的思路.     

表观基因组学研究方法进展与评价

表观遗传学是指基于非基因序列改变所致基因表达水平的变化, 如DNA甲基化和组蛋白修饰等; 表观基因组学则是在基因组水平上对表观遗传学改变的研究。DNA甲基化已经成为表观遗传学和表观基因组学的重要研究内容, 人类表观基因组计划的最终目标是绘制出人类基因组中甲基化可变位点图谱。随着研究的不断深入, 各种研究方法被开发出来以满足不同类型研究的需要。文章主要介绍目前已有的表观基因组学研究方法, 并对其进行简要分析和总结。     

中草药表观基因组学研究现状与展望

表观遗传学的实质是非DNA突变引起可继承表型变化的遗传现象.表观基因组学是在基因组水平研究表观遗传变异的科学.中草药表观基因组学是以药用植物和药用真菌为研究对象,利用分子生物学、生物信息学及"组学"相关技术,在全基因组水平上,对表观遗传修饰调控中草药次生代谢、生长发育、胁迫响应的分子机制以及中草药活性成分对生物体表观调控的药理机制进行研究的一门学科,将为解析环境因子在中药材道地性品质形成中的作用机制及中药药理新机制提供理论基础.比较表观遗传学是中草药表观基因组学研究的主要方法.本文综述了中草药表观基因组学的研究现状,探讨并展望了中草药表观基因组学研究相关成果在阐明中药材道地性的生物学实质以及中药药理新机制等方面的理论意义和应用前景.     

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。     

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.     

表观遗传与人类智力发育异常的关系概述

表观遗传学是与经典遗传学相对应的一个遗传学分支,是没有DNA序列变化的、可遗传的基因表达改变。其分子机制研究主要集中在DNA甲基化、组蛋白修饰、染色质重塑、非编码RNA的调控、X染色体失活等几个方面。表观遗传异常可导致诸多人类智力发育障碍,例如瑞特综合征、Rubinstein Taybi综合征、Beckwith-Wiedemann综合征、Prader-Willi综合征与Angelman综合征等。从疾病的临床表现、发病的遗传机制及相关治疗进展等方面对表观遗传相关人类智力发育异常疾病进行详细阐述,并对相关研究提出新的展望。     

Epigenetic modifications of metastasis suppressor genes in colon cancer metastasis

Colon and rectal cancer (colorectal cancer, CRC) is the third most common cancer worldwide. Deaths from CRC account for around 8% of all cancer deaths, making it the fourth most common cause of death from cancer. The high mortality rate of colon cancer is mainly attributable to its metastasis. Efforts have been made to identify metastasis suppressor genes, which encode proteins responsible for inhibiting the metastasis but not suppressing the growth of primary tumors. Studies on metastasis suppressor genes demonstrated that epigenetic modifications, such as DNA promoter methylation and histone modification, play crucial roles in regulating the expression of many metastasis suppressor genes, which indicates the association between aberrant epigenetic alterations and cancer metastasis. This review will focus on the recent findings regarding metastasis suppressors regulated by epigenetic modifications, particularly DNA methylation and histone modification, in CRC metastasis. Also discussed will be recent progress on the suppression of CRC metastasis by genistein, a soy isoflavone, with a focus on epigenetic mechanisms.     

DNA甲基化异常与肿瘤耐药

肿瘤耐药是导致肿瘤化疗失败的主要原因, 其产生机制复杂多样, 是多种因素共同作用的结果。近年来, 表观遗传改变在肿瘤耐药中的作用日益受到关注。DNA甲基化是一种重要的表观遗传修饰, 在调节基因表达和维持基因组稳定性中扮演着重要角色。原发性或获得性耐药的肿瘤细胞大多伴随DNA异常甲基化, 越来越多的证据显示, DNA甲基化异常是肿瘤细胞耐药表型产生的重要机制。文章就DNA甲基化异常与肿瘤细胞耐药的关系及相关作用机制进行了综述。     

Beyond regulations at DNA levels: A review of epigenetic therapeutics targeting cancer stem cells

In the past few years, the paramount role of cancer stem cells (CSCs), in terms of cancer initiation, proliferation, metastasis, invasion and chemoresistance, has been revealed by accumulating studies. However, this level of cellular plasticity cannot be entirely explained by genetic mutations. Research on epigenetic modifications as a complementary explanation for the properties of CSCs has been increasing over the past several years. Notably, therapeutic strategies are currently being developed in an effort to reverse aberrant epigenetic alterations using specific chemical inhibitors. In this review, we summarize the current understanding of CSCs and their role in cancer progression, and provide an overview of epigenetic alterations seen in CSCs. Importantly, we focus on primary cancer therapies that target the epigenetic modification of CSCs by the use of specific chemical inhibitors, such as histone deacetylase (HDAC) inhibitors, DNA methyltransferase (DNMT) inhibitors and microRNA‐based (miRNA‐based) therapeutics.     

Fundamental differences in promoter CpG island DNA hypermethylation between human cancer and genetically engineered mouse models of cancer

Genetic and epigenetic alterations are essential for the initiation and progression of human cancer. We previously reported that primary human medulloblastomas showed extensive cancer-specific CpG island DNA hypermethylation in critical developmental pathways. To determine whether genetically engineered mouse models (GEMMs) of medulloblastoma have comparable epigenetic changes, we assessed genome-wide DNA methylation in three mouse models of medulloblastoma. In contrast to human samples, very few loci with cancer-specific DNA hypermethylation were detected, and in almost all cases the degree of methylation was relatively modest compared with the dense hypermethylation in the human cancers. To determine if this finding was common to other GEMMs, we examined a Burkitt lymphoma and breast cancer model and did not detect promoter CpG island DNA hypermethylation, suggesting that human cancers and at least some GEMMs are fundamentally different with respect to this epigenetic modification. These findings provide an opportunity to both better understand the mechanism of aberrant DNA methylation in human cancer and construct better GEMMs to serve as preclinical platforms for therapy development.     

CpG Island Hypermethylation of Tumor Suppressor microRNAs in Human Cancer

In the last few years, microRNAs have started a revolution in molecular biology and emerged as key players in the cancer process. For these reasons, it is extremely important to understand the physiological and disease-associated mechanisms underlying the regulation of these small, single-stranded RNAs. Thus, it was merely a matter of time before microRNAs and epigenetics coincided. In cancer, aberrant DNA hypermethylation of tumor suppressor genes, global genomic DNA hypomethylation, and disruption of the histone modification patterns are the main epigenetic alterations, and have consequently been widely studied. Some microRNAs are downregulated in cancer and act as bona fide tumor suppressor genes, and this knowledge led to the proposal of the hypothesis that miRNAs could be silenced by epigenetic mechanisms. It has recently been shown that miR-127 and miR-124a, two putative tumor suppressor miRNAs, are methylated in tumor cells. Epigenomic tools can be effectively used in the search for new methylated tumor suppressor microRNAs. Furthermore, this aberrant methylation can be reversed by epigenetic drugs, such as DNA demethylating agents and histone deacetylase inhibitors, restoring microRNA expression levels and reverting the tumoral phenotype. In the coming years we will come to realize more fully the relevance of this expected encounter between two forces – epigenetics and microRNAs – that are currently at the forefront of biology.     

Epigenetics Alterations in Preneoplastic and Neoplastic Lesions of the Cervix

ABSTRACT: Cervical cancer (CC) is one of the most malignant tumors and the second or third most common type of cancer in women worldwide. The association between human papillomavirus (HPV) and CC is widely known and accepted (99.7% of cases). At present, the pathogenesis mechanisms of CC are not entirely clear. It has been shown that inactivation of tumor suppressor genes and activation of oncogenes play a significant role in carcinogenesis, caused by the genetic and epigenetic alterations. In the past, it was generally thought that genetic mutation was a key event of tumor pathogenesis, especially somatic mutation of tumor suppressor genes. With deeper understanding of tumors in recent years, increasing evidence has shown that epigenetic silencing of those genes, as a result of aberrant hypermethylation of CpG islands in promoters and histone modification, is essential to carcinogenesis and metastasis. The term epigenetics refers to heritable changes in gene expression caused by regulation mechanisms, other than changes in DNA sequence. Specific epigenetic processes include DNA methylation, chromotin remodeling, histone modification, and microRNA regulations. These alterations, in combination or individually, make it possible to establish the methylation profiles, histone modification maps, and expression profiles characteristic of this pathology, which become useful tools for screening, early detection, or prognostic markers in cervical cancer. This paper reviews recent epigenetics research progress in the CC study, and tries to depict the relationships between CC and DNA methylation, histone modification, as well as microRNA regulations.     

Epigenetic disruption of the WNT/ß-catenin signaling pathway in human cancers

Aberrant activation of the WNT/ß-catenin signaling pathway is frequently involved in a broad spectrum of human malignancies. Alternative to genetic deletions and point mutations, epigenetic inactivation of negative WNT regulators, through DNA methylation of promoter CpG islands and/or histone modification, leads to the activation or amplification of aberrant WNT/ß-catenin signaling. In this review, we summarized the contribution of epigenetic dysregulation of WNT/ß-catenin signaling to tumorigenesis and highlighted the importance of epigenetic identification of negative regulators of this pathway as putative tumor suppressors. The reversal of these silenced regulators may be developed as potential cancer therapeutics.     

长链非编码RNA相关表观遗传修饰在癌症中的进展*

长链非编码RNA(lncRNA)是一类转录本长度大于200 nt的RNA分子,编码蛋白质的功能有限,但其功能多样且复杂。已有研究报道lncRNA与肿瘤的发展进程密切相关,lncRNA可以通过不同方式参与细胞内生物学进程的调控,是潜在的癌症调节因子,其中,调节表观遗传修饰水平是其影响癌症进程的主要手段;癌症发病过程中细胞内存在着不同程度的表观遗传修饰,其主要为包括甲基化、乙酰化、磷酸化、糖基化、泛素化等修饰方式在内的DNA修饰、RNA修饰以及蛋白质的翻译后修饰,在癌症的不同阶段其修饰的异常程度不同,从而影响肿瘤发生的生物学进程。研究表明,lncRNA可以通过自身修饰或参与其他生物大分子的表观遗传修饰进程参与癌症的发生发展。因此,回顾了lncRNA所参与的表观遗传修饰形式和lncRNA在表观遗传修饰方面所起到的作用,并概述了lncRNA通过影响表观遗传修饰水平从而调控癌症进程的方法。旨在总结癌症细胞内表观遗传修饰方面所涉及lncRNA的研究进展,为癌症诊断和治疗提供潜在的靶标和生物学标志物。     

Bivalent histone modifications in stem cells poise miRNA loci for CpG island hypermethylation in human cancer

It has been proposed that the existence of stem cell epigenetic patterns confer a greater likelihood of CpG island hypermethylation on tumor suppressor-coding genes in cancer. The suggested mechanism is based on the Polycomb-mediated methylation of K27 of histone H3 and the recruitment of DNA methyltransferases on the promoters of tumor suppressor genes in cancer cells, when those genes are preferentially pre-marked in embryonic stem cells (ESCs) with bivalent chromatin domains. On the other hand, miRNAs appear to be dysregulated in cancer, with many studies reporting silencing of miRNA genes due to aberrant hypermethylation of their promoter regions. We wondered whether a pre-existing histone modification profile in stem cells might also contribute to the DNA methylation-associated silencing of miRNA genes in cancer. To address this, we examined a group of tumor suppressor miRNA genes previously reported to become hypermethylated and inactivated specifically in cancer cells. We analyzed the epigenetic events that take place along their promoters in human embryonic stem cells and in transformed cells. Our results suggest that there is a positive correlation between the existence of bivalent chromatin domains on miRNA promoters in ESCs and the hypermethylation of those genes in cancer, leading us to conclude that this epigenetic mark could be a mechanism that prepares miRNA promoters for further DNA hypermethylation in human tumors.     

DNA methylation in endometrial cancer

Endometrial cancer is the most commonly diagnosed gynecological cancer, and it has been shown to be a complex disease driven by abnormal genetic, and epigenetic alterations, as well as environmental factors. Epigenetic changes resulting in aberrant gene expression are dynamic and modifiable features of many cancer types. A significant epigenetic change is aberrant DNA methylation. In this review, we review evidence on the role of aberrant DNA methylation, examining changes in relation to endometrial carcinogenesis, and report on recent advances in the understanding of the contribution of aberrant DNA methylation to endometrial cancer with the emphasis on the role of dietary/ lifestyle and environmental factors, as well as opportunities and challenges of DNA methylation in endometrial cancer management and prevention.