印记控制区(ICR)的调控机制

绝大多数印记基因成簇地分布在很大的染色体区域,在发育过程中起着十分重要的作用。印记基因等位位点专一性的抑制是由印记控制区(imprinting control region,ICR)所调控的,通常是等位位点一方的ICR发生甲基化。在配子形成过程中,非组蛋白和邻近的序列会影响这种差别甲基化。DNA的甲基化、组蛋白的修饰以及多梳状体蛋白对于印记的维持十分重要。不同印记区的印记调控的方式是不同的。在某些区域ICR组装成绝缘子,干扰启动子和增强子的相互作用,而在另一些区域中涉及到了非编码RNA,印记调控以一种与X染色体失活机制类似的方式进行。     

印记基因DLK1的研究进展

在哺乳动物中,有一部分特别的基因,它们由于受到印迹而只表达单一亲本的基因,这种表观遗传的修饰现象就是基因组印记,这有别于经典的孟德尔遗传学定律。DNA甲基化是一种重要的表观遗传修饰,主要的修饰部位发生在DNA的CpG岛。它参与了细胞分化,基因组稳定性、基因印记等多种细胞生物学过程,基因印迹的建立和维持是胚胎正常发育的基础,这一过程的实现有赖于各种DNA甲基化转移酶的精确表达和密切的配合。已发现在哺乳动物的基因组中存在着许多的印记基因,DLK1基因为父系表达母源沉默的印记基因,它的表达同样受到DNA甲基化的调节,它首先在神经母细胞瘤发现并克隆,定位于人类染色体14q32,属于表皮生长因子样超家族的成员之一,约有6个外显子。研究表明,DLK1基因在胚胎肝、早期肌肉组织以及造血干细胞等组织中均有表达,人DLK1基因全长1557bp,编码序列含有1152核苷酸,编码383个氨基酸残基,在人、小鼠、绵羊都存在保守序列,它参与多种细胞的增殖、分化并且与相关肿瘤的发生发展有着密切的关系,印迹基因的印迹异常与肿瘤的易感性及发生发展有重要的关系,本文就国内外DLK1基因的研究进展做一综述。     

印记基因DLK1的研究进展

在哺乳动物中,有一部分特别的基因,它们由于受到印迹而只表达单一亲本的基因,这种表观遗传的修饰现象就是基因组印记,这有别于经典的孟德尔遗传学定律。DNA甲基化是一种重要的表观遗传修饰,主要的修饰部位发生在DNA的CpG岛,它参与了细胞分化,基因组稳定性、基因印记等多种细胞生物学过程,基因印迹的建立和维持是胚胎正常发育的基础,这一过程的实现有赖于各种DNA甲基化转移酶的精确表达和密切的配合。已发现在哺乳动物的基因组中存在着许多的印记基因,DLK1基因为父系表达母源沉默的印记基因,它的表达同样受到DNA甲基化的调节,它首先在神经母细胞瘤发现并克隆,定位于人类染色体14q32,属于表皮生长因子样超家族的成员之一,约有6个外显子。研究表明,DLK1基因在胚胎肝、早期肌肉组织以及造血干细胞等组织中均有表达,人DLK1基因全长1557bp,编码序列含有1152核苷酸,编码383个氨基酸残基,在人、小鼠、绵羊都存在保守序列,它参与多种细胞的增殖、分化并且与相关肿瘤的发生发展有着密切的关系,印迹基因的印迹异常与肿瘤的易感性及发生发展有重要的关系,本文就国内外DLK1基因的研究进展做一综述。     

基因组印记研究进展

基因组印记是由于父源或母源的等位基因受到“标记”而发生的不符合孟德尔遗传定律的特殊遗传现象。父源或母源的等位基因通过某种特异的基因修饰机制,如DNA甲基化,非编码RNA的调节作用和组蛋白修饰等,抑制另一拷贝的表达。哺乳动物中的基因印记影响着其生长发育,正常印记模式的改变在临床上会引起许多疾病。文章总结了自印记现象被发现后二十几年来的研究进展,包括印记的发生机制、发生途径、进化方式和起源理论。目前对基因印记的了解还不完全,后基因组技术的发展也许能够促进对其分子机制的进一步揭示。     

DNA甲基化与基因表达调控研究进展

表观遗传修饰是指不改变DNA序列的、可遗传的对碱基和组蛋白的化学修饰,主要包括DNA甲基化、组蛋白修饰、染色质重塑以及非编码RNA等.表观遗传修饰是更高层次的基因表达调控手段.DNA甲基化是一种重要的表观遗传修饰,参与基因表达调控、基因印记、转座子沉默、X染色体失活以及癌症发生等重要生物学过程.近年来随着研究方法和技术的进步,全基因组DNA甲基化的研究广泛兴起,多个物种全基因组甲基化图谱被破译,全局水平对DNA甲基化的研究不仅利于在宏观层面上了解DNA甲基化的特性与规律,同时也为深入分析DNA甲基化的生物学功能与调控奠定了基础.结合最新研究进展综述DNA甲基化在基因组中的分布模式、规律以及和基因转录的关系等.     

DNA甲基化——肿瘤产生的一种表观遗传学机制

在人类基因组中,DNA甲基化是一种表观遗传修饰,它与肿瘤的发生关系密切。抑癌基因和DNA修复基因的高甲基化、重复序列DNA的低甲基化、某些印记基因的印记丢失与多种肿瘤的发生有关。目前研究发现,基因组中甲基化的水平不仅受DNA 甲基化转移酶（DNMT）的影响,还与组蛋白甲基化、叶酸摄入、RNA干扰等多种因素有关。DNA甲基化在基因转录过程中扮有重要角色,并与组蛋白修饰、染色质构型重塑共同参与转录调控。     

印记基因:发育中的重要调节因子

印记基因是一类单等位表达的基因,数量少但功能强大,构成了基因组印记这一表观遗传领域中的独特现象,来源于不同亲本的印记基因在个体发育过程中承担着不同的重要功能。除了印记基因状态的建立、保持,人们围绕印记基因在发育进程中的功能做了大量研究。印记基因最初在核移植研究中被发现,早期研究聚焦在个别基因簇上。随着组学技术的引入,更多的印记基因被筛选和鉴定出来,这也引起了该领域内的热烈讨论和关注。随着全基因组DNA甲基化及组蛋白修饰等研究方法的发展,人们对印记基因的两个经典调控模型又提出新的看法和思考,尤其是最近的一些研究成果对于解释印记基因在哺乳动物中的高度保守性及其存在的意义具有重要启示。本文立足于最新研究进展,从印记基因的特征和基本规律、发育中的调控作用、机制、研究方法、进化以及环境对其影响等几个方面进行了综述,旨在为人们全面了解印记基因概况及研究趋势提供参考和指导。     

组蛋白赖氨酸甲基化在表观遗传调控中的作用

组蛋白赖氨酸的甲基化在表观遗传调控中起着关键作用。组蛋白H3的K4、K9、K27、K36、K79和H4的K20均可被甲基化。组蛋白H3第9位赖氨酸的甲基化与基因的失活相关连; 组蛋白H3第4位赖氨酸和第36位赖氨酸的甲基化与基因的激活相关连; 组蛋白H3第27位赖氨酸的甲基化与同源盒基因沉默、X染色体失活、基因印记等基因沉默现象有关; 组蛋白H3第79位赖氨酸的甲基化与防止基因失活和DNA修复有关。与此同时, 组蛋白的去甲基化也受到更为广泛的关注。 关键词: 组蛋白赖氨酸甲基转移酶; 组蛋白赖氨酸甲基化; 组蛋白去甲基化     

组蛋白去甲基化酶在发育和再生医学的研究

表观遗传学调控在器官发育以及再生医学中是重要的研究内容,而组蛋白的甲基化修饰属于表观遗传学调控机制之一并且成为近年来研究的热点内容。处于不同甲基化状态下的组蛋白,能影响多种分子对其的识别和结合,在转录起始、转录效率和转录后加工等多个层面调控相关基因的表达。而哺乳动物的器官发育与细胞重编程都与基因选择性表达密切相关,因此组蛋白甲基化状态在基因选择性表达中扮演着重要角色。本文概述了组蛋白去甲基化酶的分类以及组蛋白不同甲基化状态下对于基因的表达的调控,同时总结了组蛋白去甲基化酶在维持胚胎干细胞的多分化潜能和IPS细胞重编程效率方面的作用以及组蛋白去甲基化酶基因的缺失与相关器官发育的影响。最后探讨了组蛋白甲基化修饰酶在推动发育生物学与再生医学研究进展方面的潜能。     

基因印记与lncRNA

基因印记是一种表观遗传调控机制,在二倍体哺乳动物的发育过程中,基因印记可以调控来自亲代的等位基因差异表达。非编码RNA是不编码蛋白质的RNA,它在RNA水平调控基因表达。研究表明大多数印记基因中存在长非编码RNA（长度>200nt的非编码RNA）的转录,长非编码RNA主要通过顺式的转录干扰作用来实现基因印记。同时基因印记及其相关的长非编码RNA异常表达与许多先天疾病相关,迄今已发现数十种人类遗传疾病与基因印记有关,而lncRNA引起的基因印记在疾病的发生和治疗中起着重要作用。     

Imprinting evolution and the price of silence

In contrast to the biallelic expression of most genes, expression of genes subject to genomic imprinting is monoallelic and based on the sex of the transmitting parent. Possession of only a single active allele can lead to deleterious health consequences in humans. Aberrant expression of imprinted genes, through either genetic or epigenetic alterations, can result in developmental failures, neurodevelopmental and neurobehavioral disorders and cancer. The evolutionary emergence of imprinting occurred in a common ancestor to viviparous mammals after divergence from the egg-laying monotremes. Current evidence indicates that imprinting regulation in metatherian mammals differs from that in eutherian mammals. This suggests that imprinting mechanisms are evolving from those that were established 150 million years ago. Therefore, comparing genomic sequence of imprinted domains from marsupials and eutherians with those of orthologous regions in monotremes offers a potentially powerful bioinformatics approach for identifying novel imprinted genes and their regulatory elements. Such comparative studies will also further our understanding of the molecular evolution and phylogenetic distribution of imprinted genes.     

Comparative phylogenetic analysis of blcap/nnat reveals eutherian-specific imprinted gene

Imprinted genes are parent-of-origin dependent, monoallelically expressed genes present in marsupials and eutherian mammals. Altered expression of imprinted genes plays a significant role in the etiology of a variety of human disorders and diseases. Nevertheless, the regulatory mechanisms of imprinting remain poorly defined. The imprinted gene Neuronatin (Nnat) is an excellent candidate for studying imprinting because it resides within the 8.5-kb intron of the nonimprinted gene Bladder Cancer-Associated Protein (Blcap) and is the only imprinted gene within the region. A phylogenetic comparison of this micro-imprinted domain in human, mouse, and rat revealed several candidates for imprint control, including tandem repeats and putative binding sites for trans- acting factors known to be involved in chromatin remodeling. Genome-wide phylogenetic comparisons of species from the three major extant mammalian clades failed, however, to show any evidence of Nnat outside the eutherian lineage. Thus, Nnat is the first identified eutherian-specific imprinted gene, demonstrating that imprinted genes did not arise at a single point during evolution. This finding also suggests that the complexity of imprinting regulation observed at other loci may, in part, be directly related to the amount of time they have been imprinted.     

The origin and evolution of genomic imprinting and viviparity in mammals

Genomic imprinting is widespread in eutherian mammals. Marsupial mammals also have genomic imprinting, but in fewer loci. It has long been thought that genomic imprinting is somehow related to placentation and/or viviparity in mammals, although neither is restricted to mammals. Most imprinted genes are expressed in the placenta. There is no evidence for genomic imprinting in the egg-laying monotreme mammals, despite their short-lived placenta that transfers nutrients from mother to embryo. Post natal genomic imprinting also occurs, especially in the brain. However, little attention has been paid to the primary source of nutrition in the neonate in all mammals, the mammary gland. Differentially methylated regions (DMRs) play an important role as imprinting control centres in each imprinted region which usually comprises both paternally and maternally expressed genes (PEGs and MEGs). The DMR is established in the male or female germline (the gDMR). Comprehensive comparative genome studies demonstrated that two imprinted regions, PEG10 and IGF2-H19, are conserved in both marsupials and eutherians and that PEG10 and H19 DMRs emerged in the therian ancestor at least 160 Ma, indicating the ancestral origin of genomic imprinting during therian mammal evolution. Importantly, these regions are known to be deeply involved in placental and embryonic growth. It appears that most maternal gDMRs are always associated with imprinting in eutherian mammals, but emerged at differing times during mammalian evolution. Thus, genomic imprinting could evolve from a defence mechanism against transposable elements that depended on DNA methylation established in germ cells.     

Genomic imprinting of IGF2, p57(KIP2) and PEG1/MEST in a marsupial, the tammar wallaby

Genomic imprinting is widespread amongst mammals, but has not yet been found in birds. To gain a broader understanding of the origin and significance of imprinting, we have characterized three genes, from three separate imprinted clusters in eutherian mammals in the developing fetus and placenta of an Australian marsupial, the tammar wallaby Macropus eugenii. Imprinted gene orthologues of human and mouse p57(KIP2), IGF2 and PEG1/MEST genes were isolated. p57(KIP2) did not show stable monoallelic expression suggesting that it is not imprinted in marsupials. In contrast, there was paternal-specific expression of IGF2 in almost all tissues, but the biased paternal expression of IGF2 in the fetal head and placenta, demonstrates the occurrence of tissue-specific imprinting, as occurs in mice and humans. There was also paternal-biased expression of PEG1/MESTalpha. The differentially methylated region (DMR) of the human and mouse PEG1/MEST promoter is absent in the wallaby. These data confirm the existence of common imprinted regions in eutherians and marsupials during development, but suggest that the regulatory mechanisms that control imprinted gene expression differ between these two groups of mammals.     

Parental genomic imprinting in plants: significance for reproduction

Parental genomic imprinting is an epigenetic phenomenon causing the expression of a gene from one of the two parental alleles. Imprinting has been identified in plants and mammals. Recent evidence shows that DNA methylation and histone modifications are responsible for this parent-of-origin dependent expression of imprinted genes. We review the mechanisms and functions of imprinting in plants. We further describe the significance of imprinting for reproduction and discuss potential models for its evolution.     

Regulation and flexibility of genomic imprinting during seed development

Genomic imprinting results in monoallelic gene expression in a parent-of-origin-dependent manner. It is achieved by the differential epigenetic marking of parental alleles. Over the past decade, studies in the model systems Arabidopsis thaliana and maize (Zea mays) have shown a strong correlation between silent or active states with epigenetic marks, such as DNA methylation and histone modifications, but the nature of the primary imprint has not been clearly established for all imprinted genes. Phenotypes and expression patterns of imprinted genes have fueled the perception that genomic imprinting is specific to the endosperm, a seed tissue that does not contribute to the next generation. However, several lines of evidence suggest a potential role for imprinting in the embryo, raising questions as to how imprints are erased and reset from one generation to the next. Imprinting regulation in flowering plants shows striking similarities, but also some important differences, compared with the mechanisms of imprinting described in mammals. For example, some imprinted genes are involved in seed growth and viability in plants, which is similar in mammals, where imprinted gene regulation is essential for embryonic development. However, it seems to be more flexible in plants, as imprinting requirements can be bypassed to allow the development of clonal offspring in apomicts.     

Multilocus epimutations of imprintome in the pathology of embryo development

Genomic imprinting is one of the most significant epigenetic phenomena, which is involved in the support of eutherians and human embryo development. Molecular mechanisms of imprinting disturbance in the pathology of pre- and postnatal ontogeny are related to a considerable degree to aberrant DNA methylation of imprinted genes. At present time data about multiple abnormalities of DNA methylation arising simultaneously in several imprinted loci are accumulated. This fact brings up the problem of interpretation of imprintome structural and functional organization, as well as interaction of imprinted genes. At present study DNA methylation analysis of 51 imprinted genes in placental tissues of human spontaneous abortions was performed. The presence of several epimutations affected from four to 12 imprinted genes was observed in each embryo. Majority of epimutations (78%) had a postzygotic origin. It was shown for the first time that the total incidence of abnormal DNA methylation of maternal and paternal alleles of imprinted genes, which lead to suppression of embryo development, is significantly higher than the incidence of epimutations, which can lead to stimulation of ontogenesis processes. This fact supports at the epigenetic level the "sex conflict" hypothesis, which explains the appearance of monoallelic imprinted genes expression in the evolution of mammals.