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天下生命科学前沿动态周报（五十）
（7.25-7.31/2011）
一竞技国际集团:陶国新
主要内容：自身免疫性胃炎与幽门螺旋杆菌熏染无关；雄性激素推动了一部分女性乳腺癌的生长；定量的表观遗传影象背后的基于多梳的开关；遗传性乳腺癌遗传预期与端粒缩短相关；人体诱导多醒目细胞藏有致病性线粒体DNA突变。
焦点动态：自身免疫性胃炎与幽门螺旋杆菌熏染无关。
1. 自身免疫性胃炎与幽门螺旋杆菌熏染无关
【动态】
土耳其科学家最近研究了幽门螺旋杆菌（Hp）与自身免疫性胃炎之间的关系。经由组织学和血清学检查 ，82个Hp阳性患者和96个Hp阴性患者加入了试验。所有患者都接受了上消化道内窥镜检查。从胃窦、胃体和胃大弯取三个活组织样本做切片检查。取血清样本检查抗胃壁细胞抗体 ，抗Hp IgG和维生素B12。用学生t磨练和卡方磨练举行统计剖析。P<0.05为有统计学意义的显著差别。82个Hp阳性患者平均年岁45.1±15.1岁。Hp阳性组与阴性组之间在年岁、性别和胃体萎缩情形上无显著性差别。11个Hp阳性患者（13.4%）和14个Hp阴性患者（14.6%）抗胃壁细胞抗体阳性。两组之间无统计学意义的显著性差别（p>0.05）。壁细胞抗体阳性和阴性组之间在消化道内窥镜检查效果、胃窦胃体发炎和萎缩方面均无显著性差别（p>0.05）。该研究没有发明在幽门螺旋杆菌熏染和自身免疫性胃炎标记抗胃壁细胞抗体之间有任何关联�；剐枰憔盟娣肏p熏染患者和检测根除Hp与自身免疫性萎缩性胃炎之间的关系。
【点评】
土耳其科学家的临床研究效果为自身免疫性胃炎与幽门螺旋杆菌熏染无一定联系提供了新的证据。
【参考论文】Turk J Gastroenterol. 2011;22(2):134-8.
Is there a relationship between Helicobacter pylori and gastric autoimmunity
Erdoğan A, Yilmaz U.
Background/aims: Helicobacter pylori-associated corpus atrophy and autoimmune gastric atrophy share similar histopathologic and clinical aspects. In our study, the relation between Helicobacter pylori and autoimmune gastritis was investigated. Methods: Eighty-two consecutive histologically and serologically Helicobacter pylori-positive and 96 Helicobacter pylori-negative patients were enrolled in the study. All patients underwent diagnostic upper esophagogastroduodenal endoscopy. Three biopsy specimens from the antrum and corpus greater curvature were obtained for histologic evaluation. Serum samples were collected for detection of anti-parietal cell antibody, anti-Helicobacter pylori IgG and vitamin B12. Statistical analyses were determined with Student t-test and chi-square test. Statistical significance was determined with a p-value <0.05. Results: Of 82 Helicobacter pylori-positive patients, 45 were female and 36 were male, with a mean age 45.1 ± 15.1. There was no significant difference in age, gender and corpus atrophy between the Helicobacter pylori-positive and -negative groups. Eleven Helicobacter pylori-positive patients (13.4%) and 14 (14.6%) Helicobacter pylori-negative patients were positive for anti-parietal cell antibody; the difference between the two groups was not statistically significant (p>0.05). Differences in esophagogastroduodenal endoscopy findings, antrum and corpus inflammation, antrum and corpus atrophy, and vitamin B12 levels were found to be insignificant between parietal cell antibody-positive and -negative groups (p>0.05). Conclusions: We did not find any relation between Helicobacter pylori infection and anti-parietal cell antibody, a marker of autoimmune gastritis. Long-term follow-up of Helicobacter pylori-infected patients and also determination of the relation between eradication of Helicobacter pylori and autoimmune atrophic gastritis are needed.
2. 雄性激素推动了一部分女性乳腺癌的生长
【动态】
针对雌激素受体（ER）的激素疗法关于雌激素受体阴性的那25%到30%病人无效。在60%到70%的病人中会表达雄性激素受体（AR） ，与ER状态无关。雄性激素和AR怎样调理乳腺癌生长还很不清晰。美国科学家最近发明在ER阴性并过表达HER2的乳腺肿瘤中AR许多 ，通太过析ER-/HER2+ 的乳腺肿瘤中的AR 顺反组和雄性激素调理的基因表达 ，他们发明AR通过直接诱导转录WNT7B和HER3介导激活了配体依赖的Wnt和HER2信号通路。专门针对AR、Wnt或HER2信号损害了雄性激素刺激的肿瘤细胞生长这一征象提醒了对ER-/HER2+ 乳腺肿瘤的潜在治疗要领。这一研究发明了针对非雌激素推动的乳腺癌的进攻点。
【点评】
该研究发明了除了雌激素与乳腺癌有关 ，雄性激素与乳腺癌也有关系。为治疗雌激素受体阴性的乳腺癌患者的研究开发了蹊径。
【参考论文】Cancer Cell, 2011; 20 (1): 119-131 DOI: 10.1016/j.ccr.2011.05.026
Targeting Androgen Receptor in Estrogen Receptor-Negative Breast Cancer
Min Ni, Yiwen Chen, Elgene Lim, et al.
Endocrine therapies for breast cancer that target the estrogen receptor (ER) are ineffective in the 25% 30% of cases that are ER negative (ER ). Androgen receptor (AR) is expressed in 60% 70% of breast tumors, independent of ER status. How androgens and AR regulate breast cancer growth remains largely unknown. We find that AR is enriched in ER breast tumors that overexpress HER2. Through analysis of the AR cistrome and androgen-regulated gene expression in ER /HER2+ breast cancers we find that AR mediates ligand-dependent activation of Wnt and HER2 signaling pathways through direct transcriptional induction of WNT7B and HER3. Specific targeting of AR, Wnt or HER2 signaling impairs androgen-stimulated tumor cell growth suggesting potential therapeutic approaches for ER /HER2+ breast cancers.
3. 定量的表观遗传影象背后的基于多梳的开关
【动态】
守旧的多梳抑制复合物2（PRC2）举行的组卵白3赖氨酸27三甲基化（H3K27me3）与稳固的表观遗传静默有关。对PRC2诱导的基因静默已有许多相识 ，但要害问题照旧关于它的群集和稳固性。植物对冬天的感知和影象 ，即春化征象 ，在拟南芥是一个涉及基于PRC2的花抑制子FLC的玖犀的经典表观遗传历程。春化征象缓慢的动力学体现为在冷天需数周时间才华爆发 ，在接下来的暖日子爆发一定水平的定量取决于之前冷天长度的稳固的FLC静默。这些特点使春化征象成为理想的试验系统来研究表观遗传状态的维持和转换。英国科学家使用数学模子、染色质免疫沉淀和FLC:GUS报告剖析 ，说明晰在细胞数目取决于之前冷天数的一个细胞亚群中春化征象的数目化天性爆发于H3K27me3介导的暖天FLC静默。在冷天时代 ，在FLC上紧靠群集区域的地方H3K27me3水通常渐增添。在冷天竣事时 ，数字模拟展望这样的一个群集区域能够转换个体位置的双稳态的表观遗传状态 ，通过静默取决于冷天袒露时长的H3K27me3标记而可能涵盖整个FLC。因此 ，该模子展望了在单个细胞中FLC基因表达的一种双稳态模式 ，一种用FLC:GUS报告系统确认的展望。该研究提出的转换机制 ，涉及一个相反作用组卵白修饰的局部群集 ，很可能与普遍的表观遗传重组有关。
【点评】
该研究诠释了生物体怎样对一些转变的情形条件形成生物学影象 ，发明影象机制是一类生物学开关并能遗传给子女的表观调控。
【参考论文】Nature, 2011; DOI:10.1038/nature10241
A Polycomb-based switch underlying quantitative epigenetic memory
Andrew Angel, Jie Song, Caroline Dean, Martin Howard.
The conserved Polycomb repressive complex 2 (PRC2) generates trimethylation of histone 3 lysine 27 (H3K27me3), a modification associated with stable epigenetic silencing. Much is known about PRC2-induced silencing but key questions remain concerning its nucleation and stability. Vernalization, the perception and memory of winter in plants, is a classic epigenetic process that, in Arabidopsis, involves PRC2-based silencing of the floral repressor FLC. The slow dynamics of vernalization, taking place over weeks in the cold, generate a level of stable silencing of FLC in the subsequent warm that depends quantitatively on the length of the prior cold. These features make vernalization an ideal experimental system to investigate both the maintenance of epigenetic states and the switching between t em. Here, using mathematical modelling, chromatin immunoprecipitation and an FLC:GUS reporter assay, we show that the quantitative nature of vernalization is generated by H3K27me3-mediated FLC silencing in the warm in a subpopulation of cells whose number depends on the length of the prior cold. During the cold, H3K27me3 levels progressively increase at a tightly localized nucleation region within FLC. At the end of the cold, numerical simulations predict that such a nucleation region is capable of switching the bistable epigenetic state of an individual locus, with the probability of overall FLC coverage by silencing H3K27me3 marks depending on the length of cold exposure. Thus, the model predicts a bistable pattern of FLC gene expression in individual cells, a prediction we verify using the FLC:GUS reporter system. Our proposed switching mechanism, involving the local nucleation of an opposing histone modification, is likely to be widely relevant in epigenetic reprogramming.
4. 遗传性乳腺癌遗传预期与端粒缩短相关
【动态】
越来越多的证据批注短的端粒和响应的基因不稳固性对细胞恶性转变负有责任。家族性乳腺癌已视察到有遗传性。西班牙的科学家假设引发此病的基因缺陷会影响端粒的维护导致端粒缩短 ，研究了家族性乳腺癌病人的端粒长度。他们首先研究了623个乳腺癌家族中母女对的发病年岁预期 ，分类为BRCA1, BRCA2, 和BRCAX。别的 ， 用定量PCR剖析了198例遗传性乳腺癌病人外周血白血球中DNA端粒的长度 ，并与267例比照样本和71例偶发的乳腺癌病人样本举行了较量。同时也评估了乳腺癌家族母女对和比照样本的端粒长度转变来审查代间差别 ，发明短的端粒是遗传性而不是偶发性乳腺癌的特征。他们确定了一组带有短端粒的乳腺癌家族BRCAX ，提醒端粒维护基因可能是乳腺癌的敏感基因。值得注重的是 ，他们形貌了端粒的渐进性缩短与受影响家族一连传代时乳腺癌的越来越早爆发有联系 ，并为此提供了证据 ，提醒这可能是遗传性乳腺癌遗传预期的机理。
【点评】
该研究发明了端粒异常与遗传性乳腺癌之间的关联 ，即越来越短的端粒与越来越早爆发遗传性乳腺癌之间有关联。
【参考论文】PLoS Genetics, 2011; 7 (7): e1002182 DOI:10.1371/journal.pgen.1002182
Genetic Anticipation Is Associated with Telomere Shortening in Hereditary Breast Cancer
Beatriz Martinez-Delgado, Kira Yanowsky, Lucia Inglada-Perez, et al.
There is increasing evidence suggesting that short telomeres and subsequent genomic instability contribute to malignant transformation. Telomere shortening has been described as a mechanism to explain genetic anticipation in dyskeratosis congenita and Li-Fraumeni syndrome. Since genetic anticipation has been observed in familial breast cancer, we aimed to study telomere length in familial breast cancer patients and hypothesized that genetic defects causing this disease would affect telomere maintenance resulting in shortened telomeres. Here, we first investigated age anticipation in mother-daughter pairs with breast cancer in 623 breast cancer families, classified as BRCA1, BRCA2, and BRCAX. Moreover, we analyzed telomere length in DNA from peripheral blood leukocytes by quantitative PCR in a set of 198 hereditary breast cancer patients, and compared them with 267 control samples and 71 sporadic breast cancer patients. Changes in telomere length in mother-daughter pairs from breast cancer families and controls were also evaluated to address differences through generations. We demonstrated that short telomeres characterize hereditary but not sporadic breast cancer. We have defined a group of BRCAX families with short telomeres, suggesting that telomere maintenance genes might be susceptibility genes for breast cancer. Significantly, we described that progressive telomere shortening is associated with earlier onset of breast cancer in successive generations of affected families. Our results provide evidence that telomere shortening is associated with earlier age of cancer onset in successive generations, suggesting that it might be a mechanism of genetic anticipation in hereditary breast cancer.
5. 人体诱导多醒目细胞藏有致病性线粒体DNA突变
【动态】
人体诱导多醒目细胞最近被发明会藏有基因组修改 ，但重组细胞线粒体DNA的完整性还没有研究。线粒体DNA突变率很高 ，被以为对许多人体疾病负有责任。并且 ，线粒体DNA失去完整性可能会改变细胞的能量代谢 ，限制细胞分解。以前证实晰诱导多醒目细胞的爆发与线粒体重构和向糖解代谢转换有关的一个德国研究组最近又测定了细胞重组对线粒体DNA的完整性的影响。针对线粒体DNA的大规模平行焦磷酸测序显示泉源于年轻康健供体的人体诱导多醒目细胞藏有单个碱基的线粒体DNA突变（替换、插入、删除） ，既有同质的（在所有线粒体DNA分子）又有异质的（在一部分线粒体DNA分子）。有趣的是 ，异质性水平在泉源于统一父代纤维母细胞的诱导多醒目细胞系间也各不相同 ，这一征象很可能可用于开爆发产泉源于线粒体疾病患者的无线粒体DNA突变的诱导多醒目细胞。通过整合转录、代谢和有用的生物能量学几方面的数据 ，该研究展现了带有差别水平线粒体DNA突变的诱导多醒目细胞系维持了恒定的人体胚胎干细胞样的能量代谢重组。这包括过表达糖解酶 ，增添G6P的量 ，高表达PDK1卵白 ，从而将生物能量流线路转向糖解。总之 ，只管诱导多醒目细胞中的线粒体DNA突变不影响重组相关的代谢调解 ，在剖析诱导多醒目细胞系时致病性线粒体DNA修饰的泛起照旧要监控的一个主要方面。
【点评】
诱导多醒目细胞中的线粒体DNA突变虽不影响重组细胞的代谢蹊径调解 ，但依然保存较量高的致病危害 ，大大限制了着适用性。
【参考论文】Stem Cells, 2011; DOI:10.1002/stem.683
Human iPSCs Harbor Homoplasmic and Heteroplasmic Mitochondrial DNA Mutations While Maintaining hESC-Like Metabolic Reprogramming
Alessandro Prigione, Björn Lichtner, Heiner Kuhl, et al.
Human induced pluripotent stem cells (iPSCs) have been recently found to harbor genomic alterations. However, the integrity of mitochondrial DNA (mtDNA) within reprogrammed cells has yet to be investigated. mtDNA mutations occur at a high rate and are believed to contribute to the pathology of a number of human disorders. Furthermore, lack of mtDNA integrity may alter cellular bioenergetics and limit efficient differentiation. We previously demonstrated that the derivation of iPSCs is associated with mitochondrial remodeling and a metabolic switch towards glycolysis. Here, we aimed to determine the consequences of reprogramming on mtDNA integrity. Massively parallel pyrosequencing of mtDNA revealed that human iPSCs derived from young healthy donors harbored single base mtDNA mutations (substitutions, insertions, and deletions), both homoplasmic (in all mtDNA molecules) and heteroplasmic (in a fraction of mtDNAs). Interestingly, the level of heteroplasmy varied among iPSC lines derived from the same parental fibroblasts. This phenomenon could potentially be exploited for the generation of mtDNA mutation-free iPSCs from patients with mtDNA disorders. By integrating transcriptional, metabolic, and functional bioenergetic data, we unveiled that iPSC lines bearing different mtDNA mutational loads maintained a consistent hESC-like reprogramming of energy metabolism. This included over-expression of glycolytic enzymes, increased amount of G6P, and elevated protein expression of PDK1, which re-routes the bioenergetic flux towards glycolysis. Overall, although the mtDNA mutations within our iPSCs did not affect the reprogramming-associated metabolic modulation, the occurrence of pathogenic mtDNA modifications might be an important aspect to monitor when characterizing iPSC lines.