表观遗传学研究进展

 概述了表观遗传调节模式、表观遗传调节的效应、植物表观遗传学的研究进展等。在每种细胞中,都会发生一部分特异基因激活、另一部分基因抑制的现象,形成多种基因表达模式。表观遗传指DNA序列不发生变化,而基因表达发生可遗传改变的现象。表观遗传学改变包括DNA甲基化、组蛋白修饰、非编码RNA作用等,产生基因组印记、母性影响、基因沉默、核仁显性、休眠转座子激活等效应。表观遗传变异是环境因素和细胞内遗传物质间交互作用的结果,其效应通过调节基因表达,控制生物学表型来实现。正是因为表观修饰对于维持生物体内环境和各器官系统功能的重要性,表观遗传的异常会引发疾病,这也成为药物和治疗方案设计的着眼点。     

卵巢癌中的表观遗传修饰

介绍了在卵巢癌的发展和治疗中表观遗传学的重要性，特别强调了在卵巢癌中内源性和获得性耐药性遗传途径中异常的DNA甲基化和组蛋白去乙酰化的重要性．通过表观遗传治疗反转肿瘤抑制基因沉寂和其他参与药物级联反应的基因沉寂为出现耐药性的卵巢癌患者带来了新的希望．     

低氧与表观遗传学互作的研究进展

表观遗传学是指基因组DNA序列不发生改变的情况下,基因表达水平发生变化从而导致的可遗传表型变化的现象.表观遗传可通过与低氧诱导因子(HIF)家族协同作用,以促使细胞适应低氧环境,从而参与到低氧应答的调控过程中.现就表观遗传学通过以下四个方面与低氧应答进行综述:1)VHL与PDH3调控HIF稳定性;2)通过影响HIF-1α共激活复合物的活性、HRE位点的修饰、HIF结合位点或附近区域的染色质活性,阻止HIF与HRE位点结合;3)组蛋白脱甲基酶对低氧应答相关基因的转录调控;4)低氧环境引起细胞内整体的组蛋白修饰程度和DNA甲基化水平改变.     

A nuclear Argonaute promotes multigenerational epigenetic inheritance and germline immortality

Epigenetic information is frequently erased near the start of each new generation. In some cases, however, epigenetic information can be transmitted from parent to progeny (multigenerational epigenetic inheritance). A particularly notable example of this type of epigenetic inheritance is double-stranded RNA-mediated gene silencing in Caenorhabditis elegans. This RNA-mediated interference (RNAi) can be inherited for more than five generations. To understand this process, here we conduct a genetic screen for nematodes defective in transmitting RNAi silencing signals to future generations. This screen identified the heritable RNAi defective 1 (hrde-1) gene. hrde-1 encodes an Argonaute protein that associates with small interfering RNAs in the germ cells of progeny of animals exposed to double-stranded RNA. In the nuclei of these germ cells, HRDE-1 engages the nuclear RNAi defective pathway to direct the trimethylation of histone H3 at Lys?9 (H3K9me3) at RNAi-targeted genomic loci and promote RNAi inheritance. Under normal growth conditions, HRDE-1 associates with endogenously expressed short interfering RNAs, which direct nuclear gene silencing in germ cells. In hrde-1- or nuclear RNAi-deficient animals, germline silencing is lost over generational time. Concurrently, these animals exhibit steadily worsening defects in gamete formation and function that ultimately lead to sterility. These results establish that the Argonaute protein HRDE-1 directs gene-silencing events in germ-cell nuclei that drive multigenerational RNAi inheritance and promote immortality of the germ-cell lineage. We propose that C. elegans use the RNAi inheritance machinery to transmit epigenetic information, accrued by past generations, into future generations to regulate important biological processes.     

Molecular identification of a renal urate anion exchanger that regulates blood urate levels

Urate, a naturally occurring product of purine metabolism, is a scavenger of biological oxidants implicated in numerous disease processes, as demonstrated by its capacity of neuroprotection. It is present at higher levels in human blood (200 500 microM) than in other mammals, because humans have an effective renal urate reabsorption system, despite their evolutionary loss of hepatic uricase by mutational silencing. The molecular basis for urate handling in the human kidney remains unclear because of difficulties in understanding diverse urate transport systems and species differences. Here we identify the long-hypothesized urate transporter in the human kidney (URAT1, encoded by SLC22A12), a urate anion exchanger regulating blood urate levels and targeted by uricosuric and antiuricosuric agents (which affect excretion of uric acid). Moreover, we provide evidence that patients with idiopathic renal hypouricaemia (lack of blood uric acid) have defects in SLC22A12. Identification of URAT1 should provide insights into the nature of urate homeostasis, as well as lead to the development of better agents against hyperuricaemia, a disadvantage concomitant with human evolution.     

Identifying Micro RNA and Gene Expression Networks Using Graph Communities

Integrative network analysis is powerful in helping understand the underlying mechanisms of genetic and epigenetic perturbations for disease studies.Although it becomes clear that micro RNAs,one type of epigenetic factors,have direct effect on target genes,it is unclear how micro RNAs perturb downstream genetic neighborhood.Hence,we propose a network community approach to integrate micro RNA and gene expression profiles,to construct an integrative genetic network perturbed by micro RNAs.We apply this approach to an ovarian cancer dataset from The Cancer Genome Atlas project to identify the fluctuation of micro RNA expression and its effects on gene expression.First,we perform expression quantitative loci analysis between micro RNA and gene expression profiles via both a classical regression framework and a sparse learning model.Then,we apply the spin glass community detection algorithm to find genetic neighborhoods of the micro RNAs and their associated genes.Finally,we construct an integrated network between micro RNA and gene expression based on their community structure.Various disease related micro RNAs and genes,particularly related to ovarian cancer,are identified in this network.Such an integrative network allows us to investigate the genetic neighborhood affected by micro RNA expression that may lead to disease manifestation and progression.     

Perceptions of epigenetics

Geneticists study the gene; however, for epigeneticists, there is no obvious 'epigene'. Nevertheless, during the past year, more than 2,500 articles, numerous scientific meetings and a new journal were devoted to the subject of epigenetics. It encompasses some of the most exciting contemporary biology and is portrayed by the popular press as a revolutionary new science--an antidote to the idea that we are hard-wired by our genes. So what is epigenetics?     

Epigenetic silencers and Notch collaborate to promote malignant tumours by Rb silencing

Cancer is both a genetic and an epigenetic disease. Inactivation of tumour-suppressor genes by epigenetic changes is frequently observed in human cancers, particularly as a result of the modifications of histones and DNA methylation. It is therefore important to understand how these damaging changes might come about. By studying tumorigenesis in the Drosophila eye, here we identify two Polycomb group epigenetic silencers, Pipsqueak and Lola, that participate in this process. When coupled with overexpression of Delta, deregulation of the expression of Pipsqueak and Lola induces the formation of metastatic tumours. This phenotype depends on the histone-modifying enzymes Rpd3 (a histone deacetylase), Su(var)3-9 and E(z), as well as on the chromodomain protein Polycomb. Expression of the gene Retinoblastoma-family protein (Rbf) is downregulated in these tumours and, indeed, this downregulation is associated with DNA hypermethylation. Together, these results establish a mechanism that links the Notch-Delta pathway, epigenetic silencing pathways and cell-cycle control in the process of tumorigenesis.     

An update on histone lysine methylation in plants

Histone methylation plays crucial roles in epigenetic regulation. The SET domain proteins are now recognized as generally having methyltransferase activity targeted to specific lysine residues of histones. The enzymes and their specific histone lysine methylation have enormous impacts on the regulation of chromatin structure and function. In this review, we discuss recent advances made on histone lysine methylations and their diverse functions in plant growth and development.     

m6A修饰在骨肉瘤中分子机制的研究进展

N6-甲基腺苷(m6A)是真核生物mRNA中最丰富的表观遗传修饰之一,在多种疾病尤其是肿瘤中发挥重要作用。m6A修饰受到甲基转移酶、去甲基化酶和RNA结合蛋白的动态调控。骨肉瘤是一种好发于儿童和青少年的恶性骨肿瘤之一,近年来骨肉瘤发生率呈上升趋势,m6A修饰的调控表达与骨肉瘤的发生发展及预后相关。本文就m6A修饰在骨肉瘤发生发展、化疗耐药、靶向治疗、预后转归的分子机制方面的研究进行综述,旨在为骨肉瘤的早期诊断和靶向治疗提供新思路。     

Environmental chemical stressors as epigenome modifiers: a new horizon in assessment of toxicological effects

In eukaryotic cells, chromatin transformation from euchromatin into heterochromatin as a means of controlling gene expression and replication has been known as the ‘‘accessibility hypothesis' '. The interplay of epigenetic changes including histone modifications, DNA methylation, RNA interference(RNAi) and other func- tional epigenetic components are intricate. It is believed that these changes are well-programmed, inherited and can be modified by environmental contaminant stressors. Environmentally-driven epigenetic alterations during development, e.g. embryonic, foetal or neonatal stage, may influence disease susceptibility in adulthood. Therefore, understanding how epigenome modifications develop in response to environmental chemicals and, how epigenetic-xenobiotic interactions influence human health will shed new insights into gene-environment interactions in the epidemiology of several diseases including cancer. In this review, we consider studies of chemical modifiers including nutritional and xenobiotic effects on epigenetic components in vitro or in vivo. By examining the most-studied epigenome modifications and how their respective roles are interlinked, we highlight the central role of xenbiotic- modified epigenetic mechanisms. A major requirement will be to study and understand effects following environmentally-relevant exposures. We suggest that the study of epigenetic toxicology will open up new opportunities to devise strategies for the prevention or treatment of at-risk populations.     

小麦异源多倍体中亲本基因组相互作用产生快速基因组变异的ISSR标记分析

通过ISSR标记分析,研究了异源多倍体基因组的进化现象.结果表明,基因组组成和普通小麦相同的人工合成异源六倍体小麦,在形成早期发生了迅速、广泛、以非随机性为主的基因组变化,包括遗传变异--主要表现为序列变异和表观遗传变异--主要表现为DNA甲基化变异.而且异源六倍体小麦中来自父本的基因组比来自母本的基因组发生了更多的遗...     

A global disorder of imprinting in the human female germ line

Imprinted genes are expressed differently depending on whether they are carried by a chromosome of maternal or paternal origin. Correct imprinting is established by germline-specific modifications; failure of this process underlies several inherited human syndromes. All these imprinting control defects are cis-acting, disrupting establishment or maintenance of allele-specific epigenetic modifications across one contiguous segment of the genome. In contrast, we report here an inherited global imprinting defect. This recessive maternal-effect mutation disrupts the specification of imprints at multiple, non-contiguous loci, with the result that genes normally carrying a maternal methylation imprint assume a paternal epigenetic pattern on the maternal allele. The resulting conception is phenotypically indistinguishable from an androgenetic complete hydatidiform mole, in which abnormal extra-embryonic tissue proliferates while development of the embryo is absent or nearly so. This disorder offers a genetic route to the identification of trans-acting oocyte factors that mediate maternal imprint establishment.     

Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal human premature ageing disease, characterized by premature arteriosclerosis and degeneration of vascular smooth muscle cells (SMCs). HGPS is caused by a single point mutation in the lamin A (LMNA) gene, resulting in the generation of progerin, a truncated splicing mutant of lamin A. Accumulation of progerin leads to various ageing-associated nuclear defects including disorganization of nuclear lamina and loss of heterochromatin. Here we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts obtained from patients with HGPS. HGPS-iPSCs show absence of progerin, and more importantly, lack the nuclear envelope and epigenetic alterations normally associated with premature ageing. Upon differentiation of HGPS-iPSCs, progerin and its ageing-associated phenotypic consequences are restored. Specifically, directed differentiation of HGPS-iPSCs to SMCs leads to the appearance of premature senescence phenotypes associated with vascular ageing. Additionally, our studies identify DNA-dependent protein kinase catalytic subunit (DNAPKcs, also known as PRKDC) as a downstream target of progerin. The absence of nuclear DNAPK holoenzyme correlates with premature as well as physiological ageing. Because progerin also accumulates during physiological ageing, our results provide an in vitro iPSC-based model to study the pathogenesis of human premature and physiological vascular ageing.     

水稻表观遗传的研究进展

从DNA甲基化、组蛋白修饰的形成条件及其作用机制等方面,对表观遗传学的一些常见的发生机制进行了简要综述,并对表观遗传在水稻中研究的前景作了展望．     

RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia

Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention.     

Epigenetics in human disease and prospects for epigenetic therapy

Epigenetic mechanisms, which involve DNA and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. The study of human disease has focused on genetic mechanisms, but disruption of the balance of epigenetic networks can cause several major pathologies, including cancer, syndromes involving chromosomal instabilities, and mental retardation. The development of new diagnostic tools might reveal other diseases that are caused by epigenetic alterations. Great potential lies in the development of 'epigenetic therapies'--several inhibitors of enzymes controlling epigenetic modifications, specifically DNA methyltransferases and histone deacetylases, have shown promising anti-tumorigenic effects for some malignancies.