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Articles Online (Volume 13, Issue 6)

Research Highlight

A New Pathway for Senescence Regulation

Xi Cao, Mo Li

这是一篇针对Kang, C.等人在2015年9月25日在《科学》杂志发表论文的评论。本文简要回顾了在衰老、DNA损伤及GATA4的研究背景，并以所评论文章为重点分析其创新点和研究意义。Kang, C.的工作建立起一条经由抑制GATA4降解而调控衰老的途径，并且这是GATA4第一次被发现在该领域发挥重要作用。这些发现既有其研究意义也尤其临床意义。一方面，GATA4不再被认为只是一个参与胚胎发育调控的转录因子，它在其它生命活动中的作用也会逐渐被重视起来；另一方面，新途径为制药和治疗提供了新靶点，人们针对癌症、早衰、神经退行性病变的诊治能力也会迈上新台阶。

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Review Article

Genome Editing and Its Applications in Model Organisms

Dongyuan Ma, Feng Liu

Technological advances are important for innovative biological research. Development of molecular tools for DNA manipulation, such as zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the clustered regularly-interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas), has revolutionized genome editing. These approaches can be used to develop potential therapeutic strategies to effectively treat heritable diseases. In the last few years, substantial progress has been made in CRISPR/Cas technology, including technical improvements and wide application in many model systems. This review describes recent advancements in genome editing with a particular focus on CRISPR/Cas, covering the underlying principles, technological optimization, and its application in zebrafish and other model organisms, disease modeling, and gene therapy used for personalized medicine.
生命科学的发展依赖于生物技术不断创新与进步，而DNA操作技术的开发和应用，不仅给基因组编辑带来了革命性的突破，也为临床疾病的基因治疗提供了新方案。在这篇综述中，我们将介绍ZFNs、TALENs和CRISPR/CAS等基因编辑技术的发展和应用，重点关注新兴的CRISPR/CAS。这篇综述主要阐述CRISPR/CAS的工作原理、技术优化方案、模式生物尤其是斑马鱼中的应用现状、疾病模型构建以及基因治疗等潜在临床应用。最后，结合基因编辑技术的发展现状和优缺点，我们将探讨CRISPR/CAS应用于临床疾病治疗的可能性，着重讨论技术本身效率和特异性的改进以及潜在的安全隐患和伦理问题。

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Review Article

Urinary Biomarkers of Brain Diseases

Manxia An, Youhe Gao

Biomarkers are the measurable changes associated with a physiological or pathophysiological process. Unlike blood, urine is not subject to homeostatic mechanisms. Therefore, greater fluctuations could occur in urine than in blood, better reflecting the changes in human body. The roadmap of urine biomarker era was proposed. Although urine analysis has been attempted for clinical diagnosis, and urine has been monitored during the progression of many diseases, particularly urinary system diseases, whether urine can reflect brain disease status remains uncertain. As some biomarkers of brain diseases can be detected in the body fluids such as cerebrospinal fluid and blood, there is a possibility that urine also contain biomarkers of brain diseases. This review summarizes the clues of brain diseases reflected in the urine proteome and metabolome.
生物标志物是和疾病相关的可监测的变化。尿液因为没有稳态机制的控制。与包括血液在内的其他体液相比，尿液中含有更多的变化。其中有些变化就有可能成为疾病生物标志物。由于尿液和大脑解剖位置上较远，生理上被血脑屏障和肾脏隔开，研究人员的重视还不够，所以目前使用尿液寻找大脑生物标志物的研究较少。如果可以在尿液中寻找到可靠的大脑疾病生物标志物会给临床带来很多方便。本文综述了已有的尿蛋白质组学和尿代谢组学在大脑疾病生物标志物研究中的应用，为尿液可以作为脑疾病生物标志物的来源提供证据，为对这个方向感兴趣的科研人员提供线索。

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Research Article

Conserved Curvature of RNA Polymerase I Core Promoter Beyond rRNA Genes: The Case of the Tritryps

Pablo Smircich, María Ana Duhagon, Beatriz Garat

In trypanosomatids, the RNA polymerase I (RNAPI)-dependent promoters controlling the ribosomal RNA (rRNA) genes have been well identified. Although the RNAPI transcription machinery recognizes the DNA conformation instead of the DNA sequence of promoters, no conformational study has been reported for these promoters. Here we present the in silico analysis of the intrinsic DNA curvature of the rRNA gene core promoters in Trypanosoma brucei, Trypanosoma cruzi, and Leishmania major. We found that, in spite of the absence of sequence conservation, these promoters hold conformational properties similar to other eukaryotic rRNA promoters. Our results also indicated that the intrinsic DNA curvature pattern is conserved within the Leishmania genus and also among strains of T. cruzi and T. brucei. Furthermore, we analyzed the impact of point mutations on the intrinsic curvature and their impact on the promoter activity. Furthermore, we found that the core promoters of protein-coding genes transcribed by RNAPI in T. brucei show the same conserved conformational characteristics. Overall, our results indicate that DNA intrinsic curvature of the rRNA gene core promoters is conserved in these ancient eukaryotes and such conserved curvature might be a requirement of RNAPI machinery for transcription of not only rRNA genes but also protein-coding genes.

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Research Article

Variant rs2237892 of KCNQ1 Is Potentially Associated with Hypertension and Macrovascular Complications in Type 2 Diabetes Mellitus in A Chinese Han Population

Wanlin Zhang, Hailing Wang, Xiaomin Guan, Qing Niu, Wei Li

KCNQ1 has been identified as a susceptibility gene of type 2 diabetes mellitus (T2DM) in Asian populations through genome-wide association studies. However, studies on the association between gene polymorphism of KCNQ1 and T2DM complications remain unclear. To further analyze the association between different alleles at the single nucleotide polymorphism (SNP) rs2237892 within KCNQ1 and TD2M and its complications, we conducted a case-control study in a Chinese Han population. The C allele of rs2237892 variant contributed to susceptibility to T2DM (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.20–1.75). Genotypes CT (OR, 1.97; 95% CI, 1.24–3.15) and CC (OR, 2.49; 95% CI, 1.57–3.95) were associated with an increased risk of T2DM. Multivariate regression analysis was performed with adjustment of age, gender, and body mass index. We found that systolic blood pressure (P = 0.015), prevalence of hypertension (P = 0.037), and risk of macrovascular disease (OR, 2.10; CI, 1.00–4.45) were significantly higher in subjects with the CC genotype than in the combined population with genotype either CT or TT. Therefore, our data support that KCNQ1 is associated with an increased risk for T2DM and might contribute to the higher incidence of hypertension and macrovascular complications in patients with T2DM carrying the risk allele C though it needs further to be confirmed in a larger population.

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Letter

Association Between VDR FokI Polymorphism and Intervertebral Disk Degeneration

Jian Zhao, Mingyuan Yang, Jie Shao, Yushu Bai, Ming Li

Intervertebral disk degeneration (IDD) is strongly associated with genetic predisposition and environmental susceptibility. Several studies been conducted to investigate the potential association between IDD and FokI polymorphism located in the gene encoding the vitamin D receptor (VDR), and inconsistent conclusions had been reached among different ethnic populations. In order to assess the association between the FokI polymorphism and the risk of IDD, we performed a comprehensive and systematic meta-analysis. Candidate articles were retrieved from PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), and China Biology Medical (CBM) with strict inclusion criteria in January 2015. Among the 54 articles that were retrieved, only eight studies met the inclusion criteria. The pooled data analysis based on allele contrast, homozygote, heterozygote, dominant, and recessive models revealed no significant correlation between the FokI polymorphism and the risk of IDD. However, when stratified by ethnicity, significant associations were detected for Hispanics based on allele contrast (OR = 1.395, 95% CI = 1.059–1.836, P = 0.018), homozygote (OR = 1.849, 95% CI = 1.001–3.416, P = 0.049), heterozygote (OR = 1.254, 95% CI = 1.049–1.498, P = 0.013), and dominant (OR = 1.742, 95% CI = 1.174–2.583, P = 0.006) models, and for Asians using the dominant model (OR = 1.293, 95% CI = 1.025–1.632, P = 0.030), whereas there is no significant association detected for Caucasians. In conclusion, FokI polymorphism is not generally associated with IDD, but there is increased risk for IDD in Hispanics and Asians carrying FokI allele T.
椎间盘变性(Intervertebral disk degeneration，IDD)与遗传易感性和环境敏感性密切相关。当前有许多研究探索IDD和维生素D受体(VDR) FokI多态性的潜在关联,但是这些研究结果并不一致。为了系统评估FokI多态性和IDD的相关性,我们进行了全面、系统文献回顾和Meta分析。我们检索了PubMed、EMBASE、(CNKI),和(CBM)数据库，时间节点为2015年1月。在检索到的54篇文章中,只有8个研究符合入选标准。基于等位基因,纯合子,杂合子,显性和隐性模型，探究FokI多态性和IDD相关性。研究发现，在拉美人群中FokI多态性和IDD存在相关性(等位基因模型，OR= 1.395,95% CI = 1.059 - -1.836,P = 0.018；纯合子模型OR= 1.849,95% CI = 1.001 - -3.416,P = 0.049;杂合子模型,OR= 1.254,95% CI = 1.049 - -1.498,P = 0.013;显性模型,OR= 1.742,95% CI = 1.174 - -2.583,P = 0.006)。在亚洲人中，我们也探索到显著相关性(显性基因模型，OR= 1.293,95% CI = 1.025 - -1.632,P = 0.030);然而在高加索人群中没有发现相关性。本次研究得出, 拉美裔和亚裔携带FokI T等位基因的个体，IDD风险显著要高。

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Application Note

Diversity of Gene Expression in Hepatocellular Carcinoma Cells

Fan Zhang, Li Cui, Michael D. Kuo

Understanding tumor diversity has been a long-lasting and challenging question for researchers in the field of cancer heterogeneity or tumor evolution. Studies have reported that compared to normal cells, there is a higher genetic diversity in tumor cells, while higher genetic diversity is associated with higher progression risks of tumor. We thus hypothesized that tumor diversity also holds true at the gene expression level. To test this hypothesis, we used t-test to compare the means of Simpson’s diversity index for gene expression (SDIG) between tumor and non-tumor samples. We found that the mean SDIG in tumor tissues is significantly higher than that in the non-tumor or normal tissues (P < 0.05) for most datasets. We also combined microarrays and next-generation sequencing data for validation. This cross-platform and cross-experimental validation greatly increased the reliability of our results.
理解肿瘤多样化是肿瘤异质性和癌症进化的长期挑战的问题。研究表明与正常细胞相比，肿瘤细胞有更高的基因多样性，从而也有更高的癌症发病风险。我们因此假设肿瘤多样化在基因表达层面也成立。为了测试这个假设，我们用t-test比较肿瘤和非肿瘤样本中的基因表达的辛普森多样化指标的均值。我们发现肿瘤组织中的基因表达辛普森多样化指标的均值重要性地比正常组织和非肿瘤组织中的基因表达辛普森多样化指标的均值要高。我们同时也结合芯片和下一代测序数据作为校验。这个跨平台跨实验的校验极大地增加了我们结果的可靠性。

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