表观遗传学与肿瘤

表观遗传学是指研究基因表达或蛋白表达的改变不涉及DNA序列变化,但又可以通过细胞分裂和增殖而稳定遗传现象的遗传学分支领域。其研究对象是表观遗传修饰,目前认识到的表观遗传修饰主要包括DNA甲基化、组蛋白修饰和染色质重塑等。近年来,随着人们对表观遗传学认识的深入,尤其是DNA甲基转移酶抑制物、组蛋白乙酰化抑制剂等在治疗肿瘤患者的成功临床应用,表观遗传学逐渐成为肿瘤研究的热点。主要对DNA甲基化和组蛋白修饰两种表观遗传修饰的分子调控机制、与肿瘤发生的关系及其在肿瘤的表观遗传治疗中的研究进展作一综述。     

表观遗传学与肿瘤

表观遗传学是指研究基因表达或蛋白表达的改变不涉及DNA序列变化,但又可以通过细胞分裂和增殖而稳定遗传现象的遗传学分支领域。其研究对象是表观遗传修饰,目前认识到的表观遗传修饰主要包括DNA甲基化、组蛋白修饰和染色质重塑等。近年来,随着人们对表观遗传学认识的深入,尤其是DNA甲基转移酶抑制物、组蛋白乙酰化抑制剂等在治疗肿瘤患者的成功临床应用,表观遗传学逐渐成为肿瘤研究的热点。主要对DNA甲基化和组蛋白修饰两种表观遗传修饰的分子调控机制、与肿瘤发生的关系及其在肿瘤的表观遗传治疗中的研究进展作一综述。     

DNA甲基化的表观遗传机制及其在动物遗传育种中应用

表观遗传是一类没有产生DNA碱基序列的改变但表型特征却发生变化的调控机制,同时这种变化是可以遗传给后代的。DNA甲基化是DNA分子上的胞嘧啶在DNA甲基转移酶的作用下与一个甲基基团共价结合,被修饰为5-甲基胞嘧啶,进而调控基因表达的一种表观遗传形式。多项研究表明,DNA甲基化对动物的抗病性能、生产性能、繁殖性能均有不同程度的影响,因此探明DNA甲基化的表观遗传机制,能够为分子育种提供理论依据,将有助于更好更快的选育新品种或品系,并充分发挥其遗传潜力。     

表观遗传调控机制在犬肿瘤中的研究进展

犬肿瘤性疾病是兽医临床上常发的一种疾病，其发病率较高，是造成世界范围内犬死亡的重要原因之一，由于其病理学分类、自发性、基因和信号通路等方面与人类肿瘤有相似之处，可作为人类肿瘤的研究模型。表观遗传是基于DNA序列没有发生改变的情况下所致基因功能和表达水平发生了可遗传的变化，主要通过基因转录或翻译过程的调控，影响其功能和特性。表观遗传改变主要包括DNA甲基化水平改变、组蛋白修饰、染色质重塑和非编码RNA调控等。DNA异常甲基化在犬的多种肿瘤中均有研究，包括犬白血病、淋巴瘤及黑色素瘤等，且犬与人类肿瘤的DNA异常甲基化模式相似。在肿瘤中组蛋白各种修饰酶表达失调，是抗肿瘤药物开发分子靶点研究的主要焦点，但目前在犬肿瘤中的研究较少。非编码RNA中microRNA与lncRNA是目前的研究热点，已有较多研究致力于开发针对非编码RNA的靶向研究药物，但目前在兽医领域应用较少。作者主要综述了犬肿瘤疾病的流行病学、DNA甲基化、组蛋白修饰、非编码RNA等表观遗传学变化在犬肿瘤中的研究进展，揭示表观遗传异常与犬肿瘤发生发展的关系，以期为开发犬肿瘤性疾病诊断、靶向治疗及预后的特异性标志物提供参考依据。     

小鼠早期胚胎发育过程中的DNA去甲基化

表观遗传修饰在基因转录与表达、细胞生长与分化以及动物个体正常发育等过程中都具有重要的调控作用。表观遗传修饰发生异常,会引起机体生长发育中的各种异常。哺乳动物从精卵受精到附植前的胚胎早期发育阶段会发生重要的表观遗传重编程,主要包括DNA甲基化和组蛋白修饰。精卵受精后DNA发生主动和被动2种方式的去甲基化。本文主要综述了与DNA甲基化相关的蛋白和早期胚胎发育过程中的去甲基化机制,并对小鼠附植前胚胎发育过程中的DNA甲基化的动态变化进行了详细的论述。     

叶酸与DNA甲基化

营养表观遗传学作为表观遗传学的分支,是近年来研究很热门的一个学科。作为重要的表观遗传机制之一的DNA甲基化在营养表观遗传学及机体的生命活动中发挥着重要作用。营养素叶酸以提供甲基基团的角色参与了一碳单位的转移和利用、DNA合成及其甲基化过程,在维持基因组稳定性及机体健康状况方面起关键作用。本文旨在就叶酸生理功能及其与DNA甲基化之间的关系作简单概述。     

DNA甲基化研究进展及在羊育种中的应用

1概述 表观遗传是指在基因组序列不变的情况下,通过DNA和组蛋白的修饰等方式改变基因表达的现象,这种修饰以DNA甲基化最为常见.高等动植物中DNA甲基化主要是5-甲基胞嘧啶(5mC).在DNA甲基转移酶(DNMT)的作用下,S-腺苷甲硫氨酸(SAM)作为甲基供体,将甲基添加在DNA分子中的碱基上.5mC一般出现在CpG的胞嘧啶上.CpG位点在哺乳动物基因组中所占比例可达5％～10％,其中约有70％为mCpG.CpG位点不是均匀分布,而是呈现局部聚集倾向,形成一些CpG岛,但是大部分CpG岛不易被甲基化,而散在的CpG双核苷酸则容易被甲基化.     

DNA甲基化在动物遗传育种中的研究进展

DNA甲基化作为表观遗传学修饰方法之一,对基因的表达发挥重要的调控作用。随着众多DNA甲基化检测技术(如高通量检测技术)的迅速发展对DNA甲基化的生物信息学研究已经变成了一个非常活跃的热点。在动物遗传育种方面,由于DNA甲基化程度的改变,可能影响众多性状相关基因的表达量,因此改变动物的各种性状。所以目前已有相关研究开始探索DNA甲基化在动物遗传育种上的具体作用。     

DNA甲基化对早期胚胎发育的影响

综合分析了DNA甲基化的表观遗传特征,结合DNA甲基化在不同物种、不同发育阶段胚胎中的调控模式,以期从早期胚胎死亡角度揭示DNA甲基化作用对胚胎早期发育基因的表达调控作用,进而阐明胚胎发育过程中的表观遗传调控机制。     

DNA甲基化与生长抑制研究进展

DNA甲基化作为重要的表观遗传修饰,主要发生在CpG岛,通过DNA甲基化转移酶催化完成。DNA甲基化调控基因表达,在细胞分化、遗传印记和肿瘤的治疗等方面起着重要作用。论文概述了DNA甲基化基本概念,总结了DNA甲基化在生长抑制中的作用机制,包括降低生长相关激素的表达,阻滞细胞周期的进程,诱导细胞凋亡,阻止血管生成及抑制或激活DNA甲基化转移酶的表达和活性,展望了DNA甲基化在揭示人类疾病机制,促生长药物和抗癌药物的研发等方面的发展前景。     

Disease-dependent differently methylated regions (D-DMRs) of DNA are enriched on the X chromosome in uterine leiomyoma

Uterine leiomyoma is the most common benign tumor in women. Although responsible gene mutations have not been found in leiomyomas, they represent a progressive disease with irreversible symptoms. To characterize epigenetic features of uterine leiomyomas, the DNA methylation status of a paired sample of leiomyoma and normal myometrium was subjected to a microarray-based DNA methylation analysis with restriction tag-mediated amplification (D-REAM). In the leiomyoma, we identified an aberrant DNA methylation status for 463 hypomethylated and 318 hypermethylated genes. Although these changes occurred on all chromosomes, aberrantly hypomethylated genes were preferentially located on the X chromosome. Using paired samples of normal myometrium and leiomyoma from 6 hysterectomy patients, methylation-sensitive quantitative real-time PCR revealed 14 shared X chromosome genes with an abnormal DNA hypomethylation status (FAM9A, CPXCR1, CXORF45, TAF1, NXF5, VBP1, GABRE, DDX53, FHL1, BRCC3, DMD, GJB1, AP1S2 and PCDH11X) and one hypermethylated locus (HDAC8). Expression of XIST, which is involved in X chromosome inactivation, was equivalent in the normal myometrium and leiomyoma, indicating that the epigenetic abnormality on the X chromosome did not result from aberration of XIST gene expression. Based on these data, a unique epigenetic signature for uterine leiomyomas has emerged. The 14 hypomethylated and one hypermethylated loci provide valuable biomarkers for understanding the molecular pathogenesis of leiomyoma.     

DNA甲基化与奶牛乳腺泌乳调控的研究进展

DNA甲基化是最早发现的表观修饰方式之一,介导基因的表达沉默,在维持细胞功能、遗传印记、个体生长发育中起着重要作用。近年来,DNA甲基化参与调控乳腺生长发育及泌乳相关基因的表达,随着这方面研究的深入,DNA甲基化在奶牛生产、遗传育种方面将会有越来越多的应用。作者主要从DNA甲基化、乳腺泌乳相关基因DNA甲基化及DNA甲基化在奶牛生产中的应用进行综述。     

Epigenetic modulation of DNA methylation by nutrition and its mechanisms in animals

It is well known that phenotype of animals may be modified by the nutritional modulations through epigenetic mechanisms. As a key and central component of epigenetic network, DNA methylation is labile in response to nutritional influences. Alterations in DNA methylation profiles can lead to changes in gene expression, resulting in diverse phenotypes with the potential for decreased growth and health.Here, I reviewed the biological process of DNA methylation that results in the addition of methyl groups to DNA; the possible ways including methyl donors, DNA methyltransferase(DNMT) activity and other cofactors, the critical periods including prenatal, postnatal and dietary transition periods, and tissue specific of epigenetic modulation of DNA methylation by nutrition and its mechanisms in animals.     

DNA甲基化在哺乳动物卵母细胞和早期胚胎发育中的研究进展

DNA甲基化(DNA methylation)是一种动态、可逆并可以遗传的表观遗传修饰模式,主要发生在哺乳动物原始生殖细胞和早期胚胎发育过程中,能够通过高动态和协同的核酶网络附着在DNA的CpG区域,同时还通过改变调控区域的功能状态进而调控基因表达且不影响DNA序列所携带的遗传信息。DNA甲基化主要涉及基因组印迹、转座元件沉默、X染色体失活和衰老等多种关键生理过程,在哺乳动物卵母细胞和胚胎发育中发挥着重要作用。本文介绍了DNA甲基化的建立与去除机制及其生物学功能,重点阐述了DNA甲基化在哺乳动物卵母细胞和胚胎发育过程中精准生成、维持、读取和删除等动态变化过程,为进一步研究哺乳动物表观遗传调控提供参考依据。     

Epigenetic assessment of environmental chemicals detected in maternal peripheral and cord blood samples

Epigenetic alteration is an emerging paradigm underlying the long-term effects of chemicals on gene functions. Various chemicals, including organophosphate insecticides and heavy metals, have been detected in the human fetal environment. Epigenetics by DNA methylation and histone modifications, through dynamic chromatin remodeling, is a mechanism for genome stability and gene functions. To investigate whether such environmental chemicals may cause epigenetic alterations, we studied the effects of selected chemicals on morphological changes in heterochromatin and DNA methylation status in mouse ES cells (ESCs). Twenty-five chemicals, including organophosphate insecticides, heavy metals and their metabolites, were assessed for their effect on the epigenetic status of mouse ESCs by monitoring heterochromatin stained with 4￠,6-diamino-2-phenylindole (DAPI). The cells were surveyed after 48 or 96 h of exposure to the chemicals at the serum concentrations of cord blood. The candidates for epigenetic mutagens were examined for the effect on DNA methylation at genic regions. Of the 25 chemicals, five chemicals (diethyl phosphate (DEP), mercury (Hg), cotinine, selenium (Se) and octachlorodipropyl ether (S-421)) caused alterations in nuclear staining, suggesting that they affected heterochromatin conditions. Hg and Se caused aberrant DNA methylation at gene loci. Furthermore, DEP at 0.1 ppb caused irreversible heterochromatin changes in ESCs, and DEP-, Hg- and S-421-exposed cells also exhibited impaired formation of the embryoid body (EB), which is an in vitro model for early embryos. We established a system for assessment of epigenetic mutagens. We identified environmental chemicals that could have effects on the human fetus epigenetic status.     

Epigenetic characteristics of cloned and in vitro-fertilized swamp buffalo (Bubalus bubalis) embryos

Swamp buffalos are becoming endangered due to reproductive inefficiencies. This is of concern because many countries depend heavily on their products. Somatic cell nuclear transfer (SCNT) is a potential strategy for preserving endangered species. To date, SCNT in swamp buffalo has succeeded in the creation of blastocyst embryos. However, development to term of SCNT swamp buffalos is extremely limited, and only 1 live birth has been reported. An abnormal epigenetic mechanism is suspected to be the cause of developmental failure, as is also seen in other species. The DNA methylation and histone acetylation are key players in epigenetic modification and display marked variability during embryonic preimplantation development. Knowledge of epigenetic modifications will aid in solving the developmental problems of SCNT embryos and improving reproductive technology in the swamp buffalo. The objective of this study was to determine the relationship between preimplantation embryonic development and 2 epigenetic patterns, global DNA methylation and histone acetylation, in SCNT and in vitro-fertilized (IVF) swamp buffalo embryos. In addition, we examined the correlations between those 2 mechanisms in the SCNT and IVF swamp buffalo embryos throughout the developmental stages using double immunostaining and quantification of the emission intensities using confocal microscopy. We discovered an aberrant methylation pattern in early preimplantation-stage swamp buffalo SCNT embryos. In addition, greater variability in the DNA methylation levels among nuclei within SCNT embryos was discovered. Hyperacetylation was also observed in SCNT embryos compared with IVF embryos at the 4- and 8-cell stages (P < 0.05). Dynamic changes and interplay between these 2 epigenetic mechanisms could be crucial for embryonic development during the early preimplantation period. The aberrancies uncovered here may contribute to the low efficiency of SCNT.     

哺乳动物体细胞核移植的DNA甲基化重编程研究进展

DNA甲基化是基因组主要的表观遗传修饰方式之一.核移植重构胚在对供体细胞基因组进行甲基化重编程过程中会出现异常的甲基化模式,而异常的甲基化重编程是导致克隆胚早期死亡及克隆动物发育畸形的主要原因.论文针对体细胞克隆动物基因组DNA的甲基化模式、造成克隆胚胎甲基化异常的原因及异常甲基化对重构胚胎发育的影响等进行了综述.深入研究核移植重构胚甲基化重编程的机制,有助于完善核移植技术,提高克隆效率,使其更好地应用于基础研究和生产实践.