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。     

人消化道肿瘤的表观遗传学研究

肿瘤的发生机制中有遗传学说和表观遗传学说．后者研究的主要内容包括DNA甲基化修饰和组蛋白的各种修饰．消化道肿瘤的发生发展存在表观遗传修饰的异常,如癌基因的低甲基化和抑癌基因的高甲基化,也同时存在着组蛋白乙酰化等修饰的紊乱．通过干预表观遗传修饰防治消化道肿瘤具有广阔的应用前景．     

组蛋白甲基化的阅读器识别机制研究进展

 组蛋白甲基化修饰对遗传信息解读有着重要影响,是表观遗传调控的主要机制之一。组蛋白甲基化可以被一类称作"阅读器"的结构域所特异识别并介导下游生物学事件。本文综述了目前已知的组蛋白甲基化阅读器(包括"皇室家族"成员、PHD锌指及BAH 等结构域)的结构特征及其对于甲基化修饰位点和程度特异性识别的分子基础。另外,探讨了表观遗传修饰调控中的组合识别、修饰对话等概念与机制。     

血管衰老中的表观遗传调控

血管衰老是伴随年龄增长而出现的血管结构和功能的改变,主要包括血管重塑、血管稳态失衡以及血管细胞的衰老.表观遗传调控是在不改变DNA序列的情况下改变基因的表达,其主要机制包括DNA甲基化、组蛋白修饰以及非编码RNA的调控等.目前的研究表明各种表观遗传调控途径参与血管衰老的各个层面,在血管衰老及相关疾病的发生发展中扮演重要角色.靶向表观遗传调控的药物有望成为衰老相关疾病新的治疗方向.     

父代肥胖对精子表观遗传跨代继承的影响

父代肥胖会导致精子表观遗传修饰的改变,这种异常的表观遗传修饰会传递至后代,对后代健康产生严重影响.本文主要综述了由于父代肥胖所致的DNA甲基化、组蛋白修饰和非编码RNA等表观遗传修饰的异常及其跨代继承的机制,从表观遗传水平阐述父代肥胖对自身和后代健康的影响,可为后代相关疾病的预防和诊断提供参考资料.     

昆虫DNA甲基化研究进展

DNA甲基化作为重要的表观遗传修饰，在动植物生长发育过程中发挥着重要作用，一直是表观遗传学的研究热点.然而，有关DNA甲基化在昆虫生长发育及环境响应过程中的功能及调控机制尚不明确.针对目前已鉴定到的昆虫DNA甲基转移酶的种类及其结构、DNA甲基化作用方式及调控机制、昆虫DNA甲基化相关研究方法等进行综述，以期为后续深入了解昆虫及其他节肢动物的表观遗传调控机制提供参考.     

“表观遗传调控的分子机制”研究组——王占新研究组介绍

正表观遗传是指在不改变基因的核苷酸序列的情况下,基因表达性状的可遗传性。表观遗传信息往往通过DNA甲基化、组蛋白修饰和非编码RNA等信息进行传递,对基因的表达调控起重要作用,与机体发育和人类健康密切相关。表观遗传信息由特定的蛋白酶加载,并被特定的结合蛋白识别发挥后续效应,或者被相应的酶去除。表观遗传信息的读写异常与人类的多种疾病相关,因此,研究相关蛋白质复合物的分子机制将为揭示表观遗传调控的奥秘,以及靶向这些蛋白异常导致的人类疾病提供重要分子基础。王占新研究组主要致力于表观遗传信息的修饰以及读取过程中参与的蛋白质复合物分子机制的研究。在高等动物中,表观遗传信息往往是加载在核小体上的,     

恐惧记忆的DNA甲基化机制研究进展

综述了在恐惧记忆发生过程中DNA甲基化可能的作用机制,指出了中枢神经系统DNA甲基化的改变可以调控基因转录和海马神经发生,甚至通过精子DNA甲基化水平的改变传递给后代,从而参与恐惧记忆的表观遗传修饰.临床研究表明:人类确实存在创伤后应激障碍的代际遗传现象,结合分子生物学的研究成果.探讨了未来有望在创伤后应激障碍等精神疾病诊治上取得的进展.     

组蛋白修饰与ES细胞的多能性

胚胎干细胞（ESCs）来源于早期胚胎内细胞群，具有分化和发育多能性和无限增殖与更新能力。组蛋白修饰对ES细胞的自我更新和无限增殖能力及多能性保持具有重要作用。组蛋白修饰是表观遗传调控的关键因素，细胞通过表观遗传状态改变控制基因的选择性表达，实现对细胞分化的调控。并且可以建立调控网络调节ES细胞多能性维持。     

染色质结构及功能的变化与衰老关系的研究

有机体的所有信息全都贮存于DNA中,DNA与组蛋白及非组蛋白相复合而构成称为染色质的遗传装置。不论是组蛋白还是非组蛋白,都经历着多种合成后的共价修饰作用,一磷酸化、工酰化、ADP—核糖基化和甲基化。这些修饰作用可改变染色质的结构组织,也可改变它的模板活性。     

The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis.

Hypoxia-inducible factor-1 (HIF-1) has a key role in cellular responses to hypoxia, including the regulation of genes involved in energy metabolism, angiogenesis and apoptosis. The alpha subunits of HIF are rapidly degraded by the proteasome under normal conditions, but are stabilized by hypoxia. Cobaltous ions or iron chelators mimic hypoxia, indicating that the stimuli may interact through effects on a ferroprotein oxygen sensor. Here we demonstrate a critical role for the von Hippel-Lindau (VHL) tumour suppressor gene product pVHL in HIF-1 regulation. In VHL-defective cells, HIF alpha-subunits are constitutively stabilized and HIF-1 is activated. Re-expression of pVHL restored oxygen-dependent instability. pVHL and HIF alpha-subunits co-immunoprecipitate, and pVHL is present in the hypoxic HIF-1 DNA-binding complex. In cells exposed to iron chelation or cobaltous ions, HIF-1 is dissociated from pVHL. These findings indicate that the interaction between HIF-1 and pVHL is iron dependent, and that it is necessary for the oxygen-dependent degradation of HIF alpha-subunits. Thus, constitutive HIF-1 activation may underlie the angiogenic phenotype of VHL-associated tumours. The pVHL/HIF-1 interaction provides a new focus for understanding cellular oxygen sensing.     

A PPARγ-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis

Although feast and famine cycles illustrate that remodelling of adipose tissue in response to fluctuations in nutrient availability is essential for maintaining metabolic homeostasis, the underlying mechanisms remain poorly understood. Here we identify fibroblast growth factor 1 (FGF1) as a critical transducer in this process in mice, and link its regulation to the nuclear receptor PPARγ (peroxisome proliferator activated receptor γ), which is the adipocyte master regulator and the target of the thiazolidinedione class of insulin sensitizing drugs. FGF1 is the prototype of the 22-member FGF family of proteins and has been implicated in a range of physiological processes, including development, wound healing and cardiovascular changes. Surprisingly, FGF1 knockout mice display no significant phenotype under standard laboratory conditions. We show that FGF1 is highly induced in adipose tissue in response to a high-fat diet and that mice lacking FGF1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with a high-fat diet. Further analysis of adipose depots in FGF1-deficient mice revealed multiple histopathologies in the vasculature network, an accentuated inflammatory response, aberrant adipocyte size distribution and ectopic expression of pancreatic lipases. On withdrawal of the high-fat diet, this inflamed adipose tissue fails to properly resolve, resulting in extensive fat necrosis. In terms of mechanisms, we show that adipose induction of FGF1 in the fed state is regulated by PPARγ acting through an evolutionarily conserved promoter proximal PPAR response element within the FGF1 gene. The discovery of a phenotype for the FGF1 knockout mouse establishes the PPARγ–FGF1 axis as critical for maintaining metabolic homeostasis and insulin sensitization.     

Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia

Despite intense investigation, mechanisms that facilitate the emergence of the pre-eclampsia phenotype in women are still unknown. Placental hypoxia, hypertension, proteinuria and oedema are the principal clinical features of this disease. It is speculated that hypoxia-driven disruption of the angiogenic balance involving vascular endothelial growth factor (VEGF)/placenta-derived growth factor (PLGF) and soluble Fms-like tyrosine kinase-1 (sFLT-1, the soluble form of VEGF receptor 1) might contribute to some of the maternal symptoms of pre-eclampsia. However, pre-eclampsia does not develop in all women with high sFLT-1 or low PLGF levels, and it also occurs in some women with low sFLT-1 and high PLGF levels. Moreover, recent experiments strongly suggest that several soluble factors affecting the vasculature are probably elevated because of placental hypoxia in the pre-eclamptic women, indicating that upstream molecular defect(s) may contribute to pre-eclampsia. Here we show that pregnant mice deficient in catechol-O-methyltransferase (COMT) show a pre-eclampsia-like phenotype resulting from an absence of 2-methoxyoestradiol (2-ME), a natural metabolite of oestradiol that is elevated during the third trimester of normal human pregnancy. 2-ME ameliorates all pre-eclampsia-like features without toxicity in the Comt(-/-) pregnant mice and suppresses placental hypoxia, hypoxia-inducible factor-1alpha expression and sFLT-1 elevation. The levels of COMT and 2-ME are significantly lower in women with severe pre-eclampsia. Our studies identify a genetic mouse model for pre-eclampsia and suggest that 2-ME may have utility as a plasma and urine diagnostic marker for this disease, and may also serve as a therapeutic supplement to prevent or treat this disorder.     

一个多ON基因系统的表达动力学分析

研究了一个转录水平上的基因表达模型,它不仅考虑了启动子的复杂性,而且考虑了相互作用转录因子的调控效果.假定启动子区域有2个调控位点,启动子有1个失活态和2个激活态(即2个不同的转录出口),并考虑了绑定到不同调控位点的转录因子之间相互作用的3种代表性机制:招募机制,稳定机制和混合机制.理论分析和数值模拟结果显示:不同的转录出口能够导致mRNA分布峰的多样性; 3种机制下的平均表达水平和平均爆发频率都相同,但稳定机制诱导最大的表达噪声和平均爆发规模,而招募机制诱导最小的表达噪声和平均爆发规模.这些结果表明:细胞表型的产生源是复杂的,既与启动子结构有关也与调控机制有关.     

Central nervous system control of food intake and body weight

The capacity to adjust food intake in response to changing energy requirements is essential for survival. Recent progress has provided an insight into the molecular, cellular and behavioural mechanisms that link changes of body fat stores to adaptive adjustments of feeding behaviour. The physiological importance of this homeostatic control system is highlighted by the severe obesity that results from dysfunction of any of several of its key components. This new information provides a biological context within which to consider the global obesity epidemic and identifies numerous potential avenues for therapeutic intervention and future research.     

Oligopeptide-repeat expansions modulate 'protein-only' inheritance in yeast.

The yeast [PSI+] element represents a new type of genetic inheritance, in which changes in phenotype are transmitted by a 'protein only' mechanism reminiscent of the 'protein-only' transmission of mammalian prion diseases. The underlying molecular mechanisms for both are poorly understood and it is not clear how similar they might be. Sup35, the [PSI+] protein determinant, and PrP, the mammalian prion determinant, have different functions, different cellular locations and no sequence similarity; however, each contains five imperfect oligopeptide repeats-PQGGYQQYN in Sup35 and PHGGGWGQ in PrP. Repeat expansions in PrP produce spontaneous prion diseases. Here we show that replacing the wild-type SUP35 gene with a repeat-expansion mutation induces new [PSI+] elements, the first mutation of its type among these newly described elements of inheritance. In vitro, fully denatured repeat-expansion peptides can adopt conformations rich in beta-sheets and form higher-order structures much more rapidly than wild-type peptides. Our results provide insight into the nature of the conformational changes underlying protein-based mechanisms of inheritance and suggest a link between this process and those producing neurodegenerative prion diseases in mammals.     

Motor learning in a recurrent network model based on the vestibulo-ocular reflex.

Most models of neural networks have assumed that neurons process information on a timescale of milliseconds and that the long-term modification of synaptic strengths underlies learning and memory. But neurons also have cellular mechanisms that operate on a timescale of tens or hundreds of milliseconds, such as a gradual rise in firing rate in response to injection of constant current or a rapid rise followed by a slower adaptation. These dynamic properties of neuronal responses are mediated by ion channels that are subject to modulation. We demonstrate here how a neural network with recurrent feedback connections can convert long-term modulation of neural responses that occur over these intermediate timescales into changes in the amplitude of the steady output from the system. This general principle may be relevant to many feedback systems in the brain. Here it is applied to the vestibulo-ocular reflex, whose amplitude is subject to long-term adaptive modification by visual inputs. The model reconciles apparently contradictory data on the neural locus of the cellular mechanisms that mediate this simple form of learning and memory.     

Upwelling-driven nearshore hypoxia signals ecosystem and oceanographic changes in the northeast Pacific

Seasonal development of dissolved-oxygen deficits (hypoxia) represents an acute system-level perturbation to ecological dynamics and fishery sustainability in coastal ecosystems around the globe. Whereas anthropogenic nutrient loading has increased the frequency and severity of hypoxia in estuaries and semi-enclosed seas, the occurrence of hypoxia in open-coast upwelling systems reflects ocean conditions that control the delivery of oxygen-poor and nutrient-rich deep water onto continental shelves. Upwelling systems support a large proportion of the world's fisheries, therefore understanding the links between changes in ocean climate, upwelling-driven hypoxia and ecological perturbations is critical. Here we report on the unprecedented development of severe inner-shelf (<70 m) hypoxia and resultant mass die-offs of fish and invertebrates within the California Current System. In 2002, cross-shelf transects revealed the development of abnormally low dissolved-oxygen levels as a response to anomalously strong flow of subarctic water into the California Current System. Our findings highlight the sensitivity of inner-shelf ecosystems to variation in ocean conditions, and the potential impacts of climate change on marine communities.     

Epstein-Barr virus latent membrane protein inhibits human epithelial cell differentiation

Epstein-Barr virus (EBV), a human herpesvirus, is strongly linked with two relatively rare forms of B-cell lymphoma and with a much more prevalent epithelial malignancy, undifferentiated nasopharyngeal carcinoma (NPC). The availability of suitable culture systems has allowed detailed analysis of EBV-induced growth transformation in B lymphocytes, but little is known about the virus--epithelial cell interaction or about the possible effector role of viral proteins in the pathogenesis of NPC. Here we describe an experimental system to monitor the effects of introduced viral or cellular genes upon human epithelial cell growth and differentiation. We transfected a human epithelial cell line, which retains several features of normal keratinocyte behaviour in vitro, with the EBV gene encoding latent membrane protein (LMP), one of only two viral proteins known to be expressed in NPC cells in vivo. LMP expression was accompanied by changes in the epithelial cell surface phenotype, mimicking surface changes observed in NPC cells, and by severe impairment of the cellular response to differentiation signals. The ability of LMP to inhibit terminal differentiation indicates a mechanism whereby EBV infection of squamous epithelium could contribute to the multi-step pathogenesis of NPC.     

Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein

Viruses have developed diverse non-immune strategies to counteract host-mediated mechanisms that confer resistance to infection. The Vif (virion infectivity factor) proteins are encoded by primate immunodeficiency viruses, most notably human immunodeficiency virus-1 (HIV-1). These proteins are potent regulators of virus infection and replication and are consequently essential for pathogenic infections in vivo. HIV-1 Vif seems to be required during the late stages of virus production for the suppression of an innate antiviral phenotype that resides in human T lymphocytes. Thus, in the absence of Vif, expression of this phenotype renders progeny virions non-infectious. Here, we describe a unique cellular gene, CEM15, whose transient or stable expression in cells that do not normally express CEM15 recreates this phenotype, but whose antiviral action is overcome by the presence of Vif. Because the Vif:CEM15 regulatory circuit is critical for HIV-1 replication, perturbing the circuit may be a promising target for future HIV/AIDS therapies.