妇科肿瘤表遗传学研究进展

表遗传主要包括组蛋白乙酰化和DNA甲基化两种主要形式，目前认为组蛋白乙酰化和DNA低甲基化可促进基因表达，而组蛋白去乙酰化和DNA高甲基化可抑制基因表达。肿瘤组织中存在着基因组普遍的低甲基化和局部区域的过甲基化现象，DNA甲基化是肿瘤抑制基因失活的第三种机制，妇科肿瘤的形成与基因的表遗传明显相关。     

表基因组学(epigenomics)

指在基因组水平研究与基因表达调控相关的修饰作用的专门领域。所涉及的修饰作用主要是DNA甲基化作用和染色质的乙酰化作用、甲基化作用或磷酸化作用。DNA甲基化的主要靶点是 5’ -CpG - 3’中的C(胞嘧啶 ) ,甲基化后不改变序列顺序和密码 ,但可改变基因转录状态。染色质由核小体集合而成。核小体由DNA绕着组蛋白8面体 (由组蛋白H3、H4、2个 2A和 2B二聚体形成 )所组成。核小体中这些组蛋白末端突出 ,可发生多种修饰作用。表基因组学(epigenomics)@方福德!100005北京$中国医学科学院基础医学研究所…     

卵子发育过程中组蛋白的动态变化

表观遗传修饰是指不改变DNA序列的可逆性修饰,包括DNA甲基化、RNA干涉、基因组印迹和组蛋白密码等多方面,在生物体生长发育过程中对基因表达和调控有重要作用。在卵子发育过程中,卵母细胞经历了一系列的表观遗传动态修饰,这一表观遗传成熟过程对于卵子的减数分裂及发育能力至关重要。其中组蛋白的转录后修饰及不同组蛋白的替换对异染色质的形成及卵母细胞基因组重塑过程起关键作用。现对卵子发育过程中组蛋白甲基化、乙酰化、磷酸化等共价修饰及不同组蛋白替换的研究现状做一总结。     

卵子发育过程中组蛋白的动态变化

表观遗传修饰是指不改变DNA序列的可逆性修饰,包括DNA甲基化、RNA干涉、基因组印迹和组蛋白密码等多方面,在生物体生长发育过程中对基因表达和调控有重要作用.在卵子发育过程中,卵母细胞经历了一系列的表观遗传动态修饰.这一表观遗传成熟过程对于卵子的减数分裂及发育能力至关重要.其中组蛋白的转录后修饰及不同组蛋白的替换对异染色质的形成及卵母细胞基凼组重塑过程起关键作用.现对卵子发育过程中组蛋白甲基化、乙酰化、磷酸化等共价修饰及不同组蛋白替换的研究现状做一总结.     

DNA甲基化及其影响因素

在人类基因组中,DNA甲基化是一种重要的表遗传修饰,它与多种疾病发生密切相关。DNA甲基化在基因转录过程中起着重要的作用,与组蛋白修饰、染色质构型重塑共同参与转录调控。目前研究发现,基因组中DNA甲基化的水平与DNA甲基转移酶(DNMT)、组蛋白甲基化、饮食与环境、RNA干扰和病毒感染等多种因素有关。     

肿瘤基因启动子区异常甲基化与肿瘤的发生

肿瘤的发生和发展是一个与多基因、多步骤的致癌因素相关的复杂过程,包括了原癌基因及肿瘤抑制基因的改变、错配修复基因的突变、DNA甲基化和微卫星不稳定性。癌基因的低甲基化与抑癌基因的高甲基化在肿瘤发生、发展中的基因表达调控、基因结构的稳定等方面发挥重要作用。DNA甲基化是指生物体在DNA甲基转移酶的催化下,以S-腺苷甲硫氨酸(SAM)为甲基供体,将甲基转移到特定碱基上的过程。甲基化异常被认为是肿瘤的一个特征,是基因组中一种重要的表观遗传修饰,与肿瘤的发生、浸润及转移相关。基因局部甲基化模式的改变已成为令人瞩目的研究领域。本文就DNA甲基化及肿瘤基因启动子区甲基化研究的相关进展作简要综述。     

肥胖与营养关联的表观遗传学

肥胖是遗传与环境共同调控的代谢性疾病。表观遗传学主要研究基因表达的可遗传变化但不涉及改变DNA序列,解释部分基因-环境交互作用效应,它已成为肥胖发生发展重要预测因素。识别DNA甲基化谱、某些组蛋白修饰或其他表观遗传特征变化及其敏感饮食因素有助于预测其肥胖倾向性。     

硅转化BALB/c-3T3细胞基因组DNA异常甲基化的研究

目的 对硅转化细胞基因组DNA异常甲基化进行研究，探讨硅的表遗传致癌机制。方法 从结晶型硅(Si)转化BALB/c-3T3细胞中提取基因组DNA，经Msel(甲基化非敏感性酶)单独消化或Msel和BstU1(甲基化敏感性酶)联合消化，消化产物用甲基化敏感性内切酶指纹法(MSRF)进行分析，差异显示出异常甲基化基因片段，进一步将异常甲基化DNA片段亚克隆和序列测定，再与基因文库中的基因进行类比分析。结果发现硅转化细胞存在6条异常甲基化DNA(其中1条为高甲基化，5条有低甲基化现象)，序列测定显示这些异常甲基化基因片段似乎来源于一些RNA转录和蛋白质翻译等基因家族。结论DNA异常甲基化会导致基因表达激活或抑制，因此硅转化细胞基因组某些功能基因DNA异常甲基化导致的异常表达，可能间接是硅诱导细胞转化及其致癌作用的一种表遗传机制。     

肺癌表遗传学研究进展

表遗传学机制在肺癌的形成中占据重要地位,包括DNA的甲基化和组蛋白修饰,肺癌中与癌形成有关基因的失活多与异常甲基化有关,并且组蛋白修饰和甲基化紧密联系着。表遗传学改变多发生在肺癌早期,使得它成为肺癌化学预防的优良指标,了解肺癌表遗传现象的机制及其与传统遗传学的相互作用关系将有利于发现安全、高效的化学预防药物。     

组蛋白脱乙酰基酶及其抑制剂与宫颈癌

组蛋白乙酰化等表观遗传修饰在宫颈癌的发生及发展中具有重要作用.组蛋白脱乙酰基酶参与组成转录抑制复合物实现对多种肿瘤抑制基因表达的调节.组蛋白脱乙酰基酶与组蛋白脱乙酰基酶抑制剂通过对组蛋白乙酰化水平的调控,影响特定基因的表达,改变细胞周期的进程.组蛋白脱乙酰基酶抑制剂已被证实具有抗肿瘤作用,多种有关组蛋白脱乙酰基酶抑制剂的药物临床试验正在进行中,以期成为治疗宫颈癌的一个新方向.     

Dietary components impact histone modifications and cancer risk

Epigenetics refers to the study of heritable changes in gene expression that occur without a change in the DNA sequence and constitute an important mechanism by which dietary components can selectively activate or inactivate gene expression. Alterations in histone acetylation and methylation are a common hallmark of human cancer. This review focuses on several histone-modifying enzymes that are associated with cancer development and their modification by bioactive food components.     

Nutrition and epigenetics: An emerging field

Epigenetics refers to heritable changes to gene expression encoded not by differences in the genetic sequence but by other chemical modifications to chromatin, such as methylation of the DNA backbone, or acetylation and methylation of the histone core. The total set of such epigenetic marks can be referred to as the epigenome, but unlike the genome, epigenetic marks differ between tissues and are modified by metabolic conditions and environmental exposures throughout life. In humans and animal models, key metabolic pathways, such as those of energy metabolism and obesity, are believed to be partly regulated by epigenetic mechanisms and to be subject to metabolic and nutritional modification in utero and throughout life. There is growing interest in the possibility that extremes of energy or micronutrient availability may modulate the epigenome and hence modify the development and disease susceptibility of individuals. Particular interest is evident for methyl donors, including folic acid, which might directly modify DNA methylation in humans.     

Session 2: Personalised nutrition. Epigenomics: a basis for understanding individual differences?

Epigenetics encompasses changes to marks on the genome that are copied from one cell generation to the next, which may alter gene expression but which do not involve changes in the primary DNA sequence. These marks include DNA methylation (methylation of cytosines within CpG dinucleotides) and post-translational modifications (acetylation, methylation, phosphorylation and ubiquitination) of the histone tails protruding from nucleosome cores. The sum of genome-wide epigenetic patterns is known as the epigenome. It is hypothesised that altered epigenetic marking is a means through which evidence of environmental exposures (including nutritional status and dietary exposure) is received and recorded by the genome. At least some of these epigenetic marks are remembered through multiple cell generations and their effects may be revealed in altered gene expression and cell function. Altered epigenetic marking allows plasticity of phenotype in a fixed genotype. Despite their identical genotypes, monozygotic twins show increasing epigenetic diversity with age and with divergent lifestyles. Differences in epigenetic markings may explain some inter-individual variation in disease risk and in response to nutritional interventions.     

Methods of DNA methylation analysis

PURPOSE OF REVIEW: To provide guidance for investigators who are new to the field of DNA methylation analysis. RECENT FINDINGS: Epigenetics is the study of mitotically heritable alterations in gene expression potential that are not mediated by changes in DNA sequence. Recently, it has become clear that nutrition can affect epigenetic mechanisms, causing long-term changes in gene expression. This review focuses on methods for studying the epigenetic mechanism DNA methylation. Recent advances include improvement in high-throughput methods to obtain quantitative data on locus-specific DNA methylation and development of various approaches to study DNA methylation on a genome-wide scale. SUMMARY: No single method of DNA methylation analysis will be appropriate for every application. By understanding the type of information provided by, and the inherent potential for bias and artifact associated with, each method, investigators can select the method most appropriate for their specific research needs.     

Epigenetic abnormalities in cardiac hypertrophy and heart failure

Epigenetics refers to the heritable regulation of gene expression through modification of chromosomal components without an alteration in the nucleotide sequence of the genome. Such modifications include methylation of genomic DNA as well as acetylation, methylation, phosphorylation, ubiquitination, and SUMOylation of core histone proteins. Recent genetic and biochemical analyses indicate that epigenetic changes play an important role in the development of cardiac hypertrophy and heart failure, with dysregulation in histone acetylation status, in particular, shown to be directly linked to an impaired contraction ability of cardiac myocytes. Although such epigenetic changes should eventually lead to alterations in the expression of genes associated with the affected histones, little information is yet available on the genes responsible for the development of heart failure. Current efforts of our and other groups have focused on deciphering the network of genes which are under abnormal epigenetic regulation in failed hearts. To this end, coupling chromatin immunoprecipitation to high-throughput profiling systems is being applied to cardiac myocytes in normal as well as affected hearts. The results of these studies should not only improve our understanding of the molecular basis for cardiac hypertrophy/heart failure but also provide essential information that will facilitate the development of new epigenetics-based therapies.     

Impact of Phytochemicals and Dietary Patterns on Epigenome and Cancer

Cancer remains one of the leading causes of death around the world. Initially it is recognized as a genetic disease, but now it is known to involve epigenetic abnormalities along with genetic alterations. Epigenetics refers to heritable changes that are not encoded in the DNA sequence itself, but play an important role in the control of gene expression. It includes changes in DNA methylation, histone modifications, and RNA interference. Although it is heritable, environmental factors such as diet could directly influence epigenetic mechanisms in humans. This article will focus on the role of dietary patterns and phytochemicals that have been demonstrated to influence the epigenome and more precisely histone and non-histone proteins modulation by acetylation that helps to induce apoptosis and phosphorylation inhibition, which counteracts with cells proliferation. Recent developments discussed here enhance our understanding of how dietary intervention could be beneficial in preventing or treating cancer and improving health outcomes.     

Epigenetic modifications and human pathologies: cancer and CVD

Epigenetic changes are inherited alterations in DNA that affect gene expression and function without altering the DNA sequence. DNA methylation is one epigenetic process implicated in human disease that is influenced by diet. DNA methylation involves addition of a 1-C moiety to cytosine groups in DNA. Methylated genes are not transcribed or are transcribed at a reduced rate. Global under-methylation (hypomethylation) and site-specific over-methylation (hypermethylation) are common features of human tumours. DNA hypomethylation, leading to increased expression of specific proto-oncogenes (e.g. genes involved in proliferation or metastasis) can increase the risk of cancer as can hypermethylation and reduced expression of tumour suppressor (TS) genes (e.g. DNA repair genes). DNA methyltransferases (DNMT), together with the methyl donor S-adenosylmethionine (SAM), facilitate DNA methylation. Abnormal DNA methylation is implicated not only in the development of human cancer but also in CVD. Polyphenols, a group of phytochemicals consumed in significant amounts in the human diet, effect risk of cancer. Flavonoids from tea, soft fruits and soya are potent inhibitors of DNMT in vitro, capable of reversing hypermethylation and reactivating TS genes. Folates, a group of water-soluble B vitamins found in high concentration in green leafy vegetables, regulate DNA methylation through their ability to generate SAM. People who habitually consume the lowest level of folate or with the lowest blood folate concentrations have a significantly increased risk of developing several cancers and CVD. This review describes how flavonoids and folates in the human diet alter DNA methylation and may modify the risk of human colon cancer and CVD.     

Global DNA and p53 region-specific hypomethylation in human colonic cells is induced by folate depletion and reversed by folate supplementation

There is increasing evidence to suggest that reduced folate status may be a causative factor in carcinogenesis, particularly colorectal carcinogenesis. Folate is essential for the synthesis of S-adenosylmethionine, the methyl donor required for all methylation reactions in the cell, including the methylation of DNA. Global DNA hypomethylation appears to be an early, and consistent, molecular event in carcinogenesis. We have examined the effects of folate depletion on human-derived cultured colon carcinoma cells using 2 novel modifications to the Comet (single cell gel electrophoresis) assay to detect global DNA hypomethylation and gene region-specific DNA hypomethylation. Colon cells cultured in folate-free medium for 14 d showed a significant increase in global DNA hypomethylation compared with cells grown in medium containing 3 micromol/L folic acid. This was also true at a gene level, with folate-deprived cells showing significantly more DNA hypomethylation in the region of the p53 gene. In both cases, the effects of folate depletion were completely reversed by the reintroduction of folic acid to the cells. These results confirm that decreased folate levels are capable of inducing DNA hypomethylation in colon cells and particularly in the region of the p53 gene, suggesting that a more optimal folate status in vivo may normalize any DNA hypomethylation, offering potential protective effects against carcinogenesis. This study also introduces 2 novel functional biomarkers of DNA hypomethylation and demonstrates their suitability to detect folate depletion-induced molecular changes.     

Nutritional Epigenomics: A Portal to Disease Prevention

Epigenetics can be defined as inheritable and reversible phenomena that affect gene expression without altering the underlying base pair sequence. Epigenomics is the study of genome-wide epigenetic modifications. Because gene expression changes are critical in both normal development and disease progression, epigenetics is widely applicable to many aspects of biological research. The influences of nutrients and bioactive food components on epigenetic phenomena such as DNA methylation and various types of histone modifications have been extensively investigated. Because an individual’s epigenetic patterns are established during early gestation and are changed and personalized by environmental factors during our lifetime, epigenetic mechanisms are quite important in the development of transgenerational and adult obesity as well as in the development of diabetes mellitus. Aging and cancer demonstrate profound genome-wide DNA methylation changes, suggesting that nutrition may affect the aging process and cancer development through epigenetic mechanisms.     

基质金属蛋白酶（MMPs）基因异常甲基化与肿瘤

基质金属蛋白酶（Matrix Metalloproteinases,MMPs）是锌离子依赖内肽酶家族,几乎在人类所有肿瘤中均表达增高,并且与肿瘤转移和预后不良有关。DNA甲基化是表观遗传学的研究热点之一,是调节基因表达的重要机制。已有大量研究发现肿瘤抑制基因高甲基化与人类肿瘤中的发生发展有密切关系,然而促癌基因的低甲基化却少有相关研究。研究发现结肠癌、胰腺癌、前列腺癌、淋巴瘤中相关MMPs表达增高与DNA低甲基化有关。因此提出低甲基化可能是调节MMPs表达,促进肿瘤侵袭和转移的一个重要因素。