组蛋白赖氨酸去甲基化酶在肿瘤中的作用

在肿瘤发生过程中,组蛋白赖氨酸去甲基化酶(LSD1)的表达失调是一个重要标志。LSD1能够于组蛋白H3的N端与H3K4me2/1和H3K9me2/1相互作用,并使其去甲基化,从而调控多种不同的生理过程。同时,LSD1表达水平变化还与多种基因如p53、DNMT1和EZH2等的表达水平相关联,在胚胎发育、细胞分化和肿瘤增殖转移过程中起重要作用。     

组蛋白赖氨酸特异性去甲基化酶1 抑制剂的研究进展

组蛋白赖氨酸特异性去甲基化酶1（LSD1）能够催化氧化去除组蛋白H3K4 和H3K9 的单、双甲基,该酶在多种恶性肿瘤组织 中高度表达,与肿瘤的发生发展密切相关,是一个新兴的肿瘤治疗靶标。综述LSD1 的结构、催化机制以及近年来LSD1 抑制剂的研究进展。     

组蛋白去甲基化酶LSD1及其生物学功能

赖氨酸特异性组蛋白去甲基化酶1(Lysine specific demethylase 1, LSD1) 的发现, 表明组蛋白的甲基化修饰是一个动态可调节的过程。结构分析显示, LSD1 是一个黄素腺嘌呤二核苷酸(Flavin adenine dinulcleotide, FAD) 依赖性胺氧化酶, 它能够特异性脱去单甲基化和二甲基化组蛋白H3第4位赖氨酸(H3K4) 和H3K9 位点上的甲基基团。功能研究显示, LSD1 定位于细胞核内, 调控着基因转录的激活和抑制, 被誉为细胞深处的基因“开关”, 在胚胎发育和肿瘤发生过程中起着重要的作用。文章主要综述了LSD1 的结构、作用机制及其调控作用研究的新进展。     

赖氨酸特异性组蛋白去甲基化酶基因对蛹虫草生长发育的影响

赖氨酸特异性组蛋白去甲基化酶(lysine-specifichistonedemethylase,LSD)是真核生物中关键的表观遗传调控因子,在真菌中能够执行组蛋白特定位点上赖氨酸的去甲基化,调控多个基因的表达,从而影响多种次级代谢产物的合成。本研究通过对蛹虫草LSD基因(CmLSD)编码蛋白的生物信息学分析,发现蛹虫草CmLSD蛋白具有典型JmjC功能域,可能参与组蛋白H3、H4的去甲基化修饰。进一步对蛹虫草菌株Cm01进行CmLSD基因的过表达和敲除研究,发现该基因能够影响蛹虫草的生长和分生孢子的产生,以及腺苷、虫草素的分泌。     

PI3K/AKT信号通路调控Myogenin和MCK基因的表达

骨骼肌分化过程受多个信号通路调控, PI3K/AKT信号通路是其中最重要的信号转导通路之一。PI3K/AKT信号通路可以调控骨骼肌分化, 但在染色质水平上的调控机制还不是很清楚。文章以小鼠成肌细胞(C2C12)为研究材料, 采用免疫印迹、染色质免疫共沉淀(Chromatin immunoprecipitation, ChIP)、定量PCR (Q-PCR)的方法研究PI3K/AKT信号通路调控Myogenin和MCK基因的表达。研究发现, C2C12细胞分化过程中添加PI3K/AKT信号通路激活剂处理24 h, Myogenin和MCK蛋白表达水平显著升高, 组蛋白H3K27me3去甲基化酶UTX的表达也升高, H3K27me3在Myogenin基因启动子区和MCK基因启动子及增强子区的富集与对照组相比显著降低。用PI3K/AKT信号通路抑制剂处理, 结果相反。因此, PI3K/AKT信号通路可能通过调控组蛋白去甲基化酶UTX的表达活性改变靶基因的H3K27me3的富集进而调控骨骼肌分化。     

雷公藤内酯醇对多发性骨髓瘤细胞凋亡及组蛋白H3K4甲基化的影响

目的：探讨雷公藤内酯醇（TPL）对多发性骨髓瘤RPMI8226细胞增殖、凋亡和组蛋白H3K4甲基化的影响。方法：以人多发性骨髓瘤细胞株RPMI8226为研究对象,在不同浓度（10、20、40、80、160 nmol/L） TPL中共培养不同时间（24 h、48 h、72 h）后,采用噻唑蓝（MTT）法检测细胞增殖活性;流式细胞术检测细胞凋亡和细胞周期;Western blot法检测组蛋白H3K4me2、H3K4me3的甲基化状态,实时荧光定量RT-PCR分析组蛋白甲基化酶SMYD3和组蛋白去甲基化酶LSD1的表达水平。结果：TPL对RPMI8226细胞有明显的增殖抑制作用,呈剂量和时间依赖性（P<0.05）;TPL对RPMI8226细胞有明显诱导凋亡的作用,并且随着TPL作用浓度的增加,细胞凋亡比例逐渐增加（P<0.05）;同时TPL还可以诱导RPMI8226细胞周期阻滞于G₂/M期;TPL以浓度依赖性降低组蛋白H3K4me2、H3K4me3的甲基化水平（P<0.05,P<0.01）,并抑制SMYD3和上调LSD1的表达（P<0.05）。结论：TPL可抑制RPMI8226细胞增殖、引起细胞周期阻滞于G₂/M期,并诱导其凋亡;通过抑制组蛋白甲基化酶SMYD3和增强组蛋白去甲基化酶LSD1的表达,降低组蛋白H3K4me3和H3K4me2的甲基化水平,这可能是TPL诱导多发性骨髓瘤细胞凋亡和抗肿瘤作用的机制之一。     

赖氨酸特异性组蛋白去甲基化酶1作用机制及其生物学功能的研究进展

与其他化学修饰,如乙酰化、磷酸化、泛素化等相似,组蛋白赖氨酸甲基化是一个可以逆转的组蛋白修饰,是一个动态调节的过程。赖氨酸特异性组蛋白去甲基化酶1（lysine specific demethylase 1,LSD1）是一个黄素腺嘌呤二核苷酸（flavin adenine dinulcleotide,FAD）依赖性胺氧化酶,它能够特异性脱去H3K4和H3K9位点上的单甲基化和二甲基化的甲基基团。LSD1参与调控核受体介导的基因转录,并分别维持染色质的活性和非活性状态,被誉为细胞深处的基因＂开关＂。LSD1的功能失衡可引发多种重要生命现象的改变。主要综述LSD1的结构、作用机制及其在肿瘤发生、胚胎发育、体细胞重编程的调控、细胞分裂和造血等过程中生物学功能的研究新进展。     

组蛋白赖氨酸甲基转移酶2D调控H9c2细胞中HIF-1α/VEGF通路（英文）

组蛋白赖氨酸甲基转移酶2D (histone-lysine N-methyltransferase 2D, KMT2D)作为主要的组蛋白3第4位赖氨酸(H3K4)甲基转移酶,在调控胚胎发育、组织分化、代谢和肿瘤抑制方面发挥重要作用。在小鼠体内,敲除Kmt2d会导致严重的心脏发育缺陷最终造成胚胎期死亡。低氧诱导因子-1α(hypoxia-inducible factor 1α, HIF-1α)作为调节细胞应对低氧的关键转录因子,能够调控多种下游基因转录。有相关研究揭示,表观遗传调控者能够调节HIF-1α的稳定性和活性。同样,作为表观遗传调控者的组蛋白甲基转移酶KMT2D是否参与低氧条件下HIF-1α对下游基因的调控,目前仍未知。在本研究中,观察在Kmt2d正常或缺乏的情况下,心肌细胞H9c2对低氧环境的应答反应。结果显示,与常氧条件相比,低氧状态下HIF-1α、组蛋白乙酰化酶P300、KMT2D及其介导的H3K4一甲基化(H3K4 mono-methylation, H3K4me1)的蛋白质水平增加(P0.05);HIF-1α下游基因血管内皮生长因子(vascular endothelial growth factor, Vegf)的mRNA表达水平明显上调(P0.01)。染色质免疫共沉淀实验(chromatin immunoprecipitation assay, ChIP-qPCR)检测结果显示,H3K4me1和组蛋白3第27位赖氨酸乙酰化(histone 3 lysine 27 acetylation, H3K27ac)在Vegf基因启动子区域的结合丰度明显增加(P0.05)。低氧条件下沉默Kmt2d之后,H3K4me1蛋白水平和Vegf的mRNA表达下降(P0.05)。本研究表明,低氧条件下KMT2D参与调控HIF-1α和下游基因Vegf的表达。     

组蛋白H3K27去甲基化酶与肿瘤发生

组蛋白甲基化是一种重要的表观遗传学修饰,在基因表达调节方面发挥着重要的作用.组蛋白H3赖氨酸27三甲基化（H3K27me3）是一种抑制性组蛋白标记,可被去甲基化酶UTX和JMJD3催化而移去甲基.UTX和JMJD3通过激活HOX基因而参与细胞分化和多能细胞抑制过程.在多种肿瘤中检测到UTX和JMJD3突变或表达下降,同时多种基因启动子区H3K27me3含量增多.UTX和JMJD3均被看作肿瘤抑制基因,其中UTX调节了RB依赖的细胞命运控制,而JMJD3通过激活INK4b-ARF-INK4a位点而参与了癌基因诱导的衰老.组蛋白H3K27去甲基化酶与肿瘤发生的研究使我们对癌症发展过程有了更好的理解,同时也为癌症诊断和治疗提供了新靶点.     

Role for dopamine in malonate-induced damage in vivo in striatum and in vitro in mesencephalic cultures

Defects in mitochondrial energy metabolism have been implicated in the pathology of several neurodegenerative disorders. In addition, the reactive metabolites generated from the metabolism and oxidation of the neurotransmitter dopamine (DA) are thought to contribute to the damage to neurons of the basal ganglia. We have previously demonstrated that infusions of the metabolic inhibitor malonate into the striata of mice or rats produce degeneration of DA nerve terminals. In the present studies, we demonstrate that an intrastriatal infusion of malonate induces a substantial increase in DA efflux in awake, behaving mice as measured by in vivo microdialysis. Furthermore, pretreatment of mice with tetrabenazine (TBZ) or the TBZ analogue Ro 4-1284 (Ro-4), compounds that reversibly inhibit the vesicular storage of DA, attenuates the malonate-induced DA efflux as well as the damage to DA nerve terminals. Consistent with these findings, the damage to both DA and GABA neurons in mesencephalic cultures by malonate exposure was attenuated by pretreatment with TBZ or Ro-4. Treatment with these compounds did not affect the formation of free radicals or the inhibition of oxidative phosphorylation resulting from malonate exposure alone. Our data suggest that DA plays an important role in the neurotoxicity produced by malonate. These findings provide direct evidence that inhibition of succinate dehydrogenase causes an increase in extracellular DA levels and indicate that bioenergetic defects may contribute to the pathogenesis of chronic neurodegenerative diseases through a mechanism involving DA.     

2018年中国植物科学若干领域重要研究进展

2018年中国植物科学继续呈现快速发展的态势, 我国科学家在国际植物科学主流学术刊物发表论文数量大幅增加, 取得了多项具有重要影响的成果。调控植物生长-代谢平衡实现可持续农业发展入选2018年度中国科学十大进展; 中国被子植物区系进化历史研究入选2018年度中国生命科学十大进展。以水稻为代表的农作物和果蔬等经济作物研究在国际上已呈现出明显的优势, 若干领域已从“追赶”状态跨越到“领跑”地位。该文对2018年中国科学家在植物科学若干领域取得的重要研究成果进行了概括性评述, 旨在全面追踪和报道当前中国植物科学领域的发展前沿和热点, 展示中国科学家所取得的杰出成就。     

2017年中国植物科学若干领域重要研究进展

2017年中国植物科学继续保持高速发展态势, 重大成果频出, 具体表现在中国植物学家在国际顶级学术期刊发表的文章数量平稳上升。中国植物科学领域的研究工作者成果精彩纷呈, 如新型广谱抗病机制的发现、水稻广谱抗病遗传基础及机制和疫霉菌诱发病害成灾机制研究等。2017年中国生命科学领域十大进展评选中, 有两项植物科学领域的研究成果入选。水稻生物学、进化与基因组学和激素生物学等领域学科发展突出。另外, 值得一提的是, 长期从事高等植物与代谢途径调控分子网络研究和水稻品种设计育种的李家洋院士的研究成果“水稻高产优质性状形成的分子机理及品种设计”荣获2017年国家自然科学一等奖。这一具有重大国际影响的开创性贡献标志着中国植物科学在该领域的国际科学前沿居于引领和卓越地位。该文对2017年中国本土科学家在植物科学若干领域取得的重要研究成果进行了系统梳理, 旨在全面追踪和报道当前中国植物科学领域发展的最新前沿动态, 与广大读者共同分享我国科学家所取得的辉煌成就。     

我国葫芦科植物离体培养研究进展

葫芦科植物包括多种瓜类蔬菜,对其进行离体培养研究具有重要的理论和实践意义。综述了国内在葫芦科植物器官培养、体细胞胚胎发生、花药培养、原生质体培养和体细胞杂交及离体遗传转化等方面取得的研究进展,并对葫芦科植物离体培养、遗传转化与育种的前景作了展望。     

SSTR5 ablation in islet results in alterations in glucose homeostasis in mice

Somatostatin (SST) peptide is a potent inhibitor of insulin secretion and its effect is mediated via somatostatin receptor 5 (SSTR5) in the endocrine pancreas. To investigate the consequences of gene ablation of SSTR5 in the mouse pancreas, we have generated a mouse model in which the SSTR5 gene was specifically knocked down in the pancreatic beta cells (betaSSTR5Kd) using the Cre-lox system. Immunohistochemistry analysis showed that SSTR5 gene expression was absent in beta cells at three months of age. At the time of gene ablation, betaSSTR5Kd mice demonstrated glucose intolerance with lack of insulin response and significantly reduced serum insulin levels. Insulin tolerance test demonstrated a significant increase of insulin clearance in vivo at the same age. In vitro studies demonstrated an absence of response to SST-28 stimulation in the betaSSTR5Kd mouse islet, which was associated with a significantly reduced SST expression level in betaSSTR5Kd mice pancreata. In addition, betaSSTR5Kd mice had significantly reduced serum glucose levels and increased serum insulin levels at 12 months of age. Glucose tolerance test at an older age also indicated a persistently higher insulin level in betaSSTR5Kd mice. Further studies of betaSSTR5Kd mice had revealed elevated serum C-peptide levels at both 3 and 12 months of age, suggesting that these mice are capable of producing and releasing insulin to the periphery. These results support the hypothesis that SSTR5 plays a pivotal role in the regulation of insulin secretion in the mouse pancreas.     

2018年中国植物科学若干领域重要研究进展

2018年中国植物科学继续呈现快速发展的态势, 我国科学家在国际植物科学主流学术刊物发表论文数量大幅增加, 取得了多项具有重要影响的成果。调控植物生长-代谢平衡实现可持续农业发展入选2018年度中国科学十大进展; 中国被子植物区系进化历史研究入选2018年度中国生命科学十大进展。以水稻为代表的农作物和果蔬等经济作物研究在国际上已呈现出明显的优势, 若干领域已从“追赶”状态跨越到“领跑”地位。该文对2018年中国科学家在植物科学若干领域取得的重要研究成果进行了概括性评述, 旨在全面追踪和报道当前中国植物科学领域的发展前沿和热点, 展示中国科学家所取得的杰出成就。     

我国葫芦科植物离体培养研究进展

葫芦科植物包括多种瓜类蔬菜,对其进行离体培养研究具有重要的理论和实践意义.综述了国内在葫芦科植物器官培养、体细胞胚胎发生、花药培养、原生质体培养和体细胞杂交及离体遗传转化等方面取得的研究进展,并对葫芦科植物离体培养、遗传转化与育种的前景作了展望.     

Changes in aquatic vegetation in Rhine floodplain streams in Alsace in relation to disturbance

Abstract. Changes are described in aquatic vegetation in oligotrophic, groundwater-fed Rhine floodplain streams in Alsace (eastern France), resulting from disturbance. Disturbance factors include changes in nutrients, either permanent ones - effluent from a waste water treatment plant or trout hatcheries - or periodic ones: flooding. Regular inputs of high levels of phosphate and ammonia modified the macrophyte vegetation in these streams. The floristic composition, which was characteristic of oligotrophic waters upstream of the eutrophicated sector, changed to that of a eutrophic situation as originally found downstream. Periodic disturbance by floods which normally occur once a year, irregularly eutrophicates the small streams, causing the development of a mixture of eutrophic and oligotrophic species. Six macrophyte communities are distinguished, indicating different trophic levels. The aquatic vegetation is adapted to the variations of phosphate and ammonia levels. Hence, aquatic macrophytes can be used as bio-indicators of fluctuations in water nutrient levels in relation to the type of disturbance.     

Apoptosis in experimental myocardial infarction in situ and in the perfused heart in vitro

We report the appearance of apoptotic cells in experimental myocardial infarction (rabbit heart) in in situ and in vitro preparations. Apoptosis was recognized by intravital staining with Hoechst 33342 (Ho342), by nick-end labeling (TUNEL) and by DNA laddering. A steady rise in the relative number of apoptotic cardiomyocytes (apoptotic index) was noted in in situ preparations. Apoptosis was first noted 6 h after the onset of ischemia with its highest value occurring after 72 h. Apoptotic nuclei were absent in remote areas of the left and right ventricles. Apoptotic nuclei within the infarcted area showed diminished intensity of Ho342 fluorescence. Three days after ischemia, a border zone adjacent to the infarcted area consisting of apoptotic macrophages was recognized. A novel finding was the appearance of apoptotic cardiomyocytes in the isolated perfused ischemic heart. Occurring as early as 50 min after the onset of ischemia, a high apoptotic index was present adjacent to the ligature placed around the coronary artery. This observation provides the opportunity to selectively examine factors leading to apoptosis in the ischemic heart under controlled experimental conditions.     

Morphine-potentiated platelet aggregation in in vitro and platelet plug formation in in vivo experiments

The detailed mechanisms underlying morphine-signaling pathways in platelets remain obscure. Therefore, we systematically examined the influence of morphine on washed human platelets. In this study, washed human platelet suspensions were used for in vitro studies. Furthermore, platelet thrombus formation induced by irradiation of mesenteric venules with filtered light in mice pretreated with fluorescein sodium was used for an in vivo thrombotic study. Morphine concentration dependently (0.6, 1, and 5 microM) potentiated platelet aggregation and the ATP release reaction stimulated by agonists (i.e., collagen and U46619) in washed human platelets. Yohimbine (0.1 microM), a specific alpha(2)-adrenoceptor antagonist, markedly abolished the potentiation of morphine in platelet aggregation stimulated by agonists. Morphine also potentiated phosphoinositide breakdown and intracellular Ca(2+) mobilization in human platelets stimulated by collagen (1 microg/ml). Moreover, morphine (0.6-5 microM) markedly inhibited prostaglandin E(1) (10 microM)-induced cyclic AMP formation in human platelets, while yohimbine (0.1 microM) significantly reversed the inhibition of cyclic AMP by morphine (0.6 and 1 microM) in this study. The thrombin-evoked increase in pH(i) was markedly potentiated in the presence of morphine (1 and 5 microM). Morphine (2 and 5 mg/g) significantly shortened the time require to induce platelet plug formation in mesenteric venules. We concluded that morphine may exert its potentiation in platelet aggregation by binding to alpha(2)-adrenoceptors in human platelets, with a resulting inhibition of adenylate cyclase, thereby reducing intracellular cyclic AMP formation followed by increased activation of phospholipase C and the Na(+)/H(+) exchanger. This leads to increased intracellular Ca(2+) mobilization, and finally potentiation of platelet aggregation and of the ATP release reaction.