microsatellite

微卫星
  • 文章类型: Journal Article
    这项研究的目的是评估立陶宛园艺研究所农业和林业研究中心(LRCAFIH)开发的13个番茄(SolanumlycopersicumL.)品种和6个杂种的表型性状和遗传多样性。对于分子表征,使用了七个以前发表的微卫星标记(SSR)。在番茄品种和杂种中检测到A24和26个等位基因,分别。基于多态性信息含量(PIC)值,品种信息最多的SSR引物是TMS52,TGS0007,LEDDNa和Tom236-237,杂种信息最多的SSR引物是SSR248和TMS52。在UPGMA聚类分析中,在某些情况下,由于遗传关系,番茄品种被分组,作为相同的集群品种“Viltis”(简历的亲本。\'Laukiai\')和\'Aušriai\'(简历的后代。\'Jurgiai\')在场。树状图中所有杂种的分组与亲本形式有关,它显示了分子标记对番茄育种的有用性,因为它们可以用来追踪杂种的起源,最终,品种准确。有关立陶宛番茄品种遗传背景的知识将有助于在番茄育种计划中计划有针对性的杂交。
    The aim of this study was to evaluate phenotypic traits and genetic diversity of the 13 tomato (Solanum lycopersicum L.) varieties and 6 hybrids developed at the Institute of Horticulture Lithuanian Research Centre for Agriculture and Forestry (LRCAF IH). For the molecular characterisation, seven previously published microsatellite markers (SSR) were used. A24 and 26 alleles were detected in tomato varieties and hybrids, respectively. Based on the polymorphism information content (PIC) value, the most informative SSR primers for varieties were TMS52, TGS0007, LEMDDNa and Tom236-237, and the most informative SSR primers for hybrids were SSR248 and TMS52. In UPGMA cluster analysis, tomato varieties are grouped in some cases due to genetic relationships, as the same cluster cultivars \'Viltis\' (the parent of cv. \'Laukiai\') and \'Aušriai\' (the progeny of cv. \'Jurgiai\') are present. The grouping of all hybrids in the dendrogram is related to the parental forms, and it shows the usefulness of molecular markers for tomato breeding, as they can be used to trace the origin of hybrids and, eventually, varieties accurately. The knowledge about the genetic background of Lithuanian tomato cultivars will help plan targeted crosses in tomato breeding programs.
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  • 文章类型: Journal Article
    几百年来,猫已经被驯化和选择性饲养,最近的猫表演和繁殖协会加速了许多纯种品种。人们对有限的育种选择和近亲繁殖的遗传影响提出了担忧,表明在纯种猫中保持遗传多样性和准确鉴定方面存在挑战。在这项研究中,使用15个微卫星标记和线粒体DNA(mtDNA)D环测序在5个泰国家猫品种中检查了遗传变异性和结构。总的来说,代表WichienMaat(WCM)的184个样本,Suphalak(SL),Khao-Manee(KM),Korat(KR),并对Konja(KJ)品种进行了分析。在所有品种中观察到高遗传多样性(Ho和He>0.5),mtDNA分析揭示了泰国和全球所有家猫品种共有的两个主要单倍群(A和B)。然而,根据聚类分析,观察到泰国家猫品种之间的微小差异,其中在WCM品种中观察到独特的遗传结构。这表明,在具有共同种族起源的偏远地区出现的泰国家猫品种中,已经发生了针对独特形态特征的等位基因固定。对该品种中个体之间关系的分析显示,泰国家猫品种的鉴定效率高(P(ID)同胞<10-4)。此外,通过仅使用9个基因座优化标记效率,可以确保多样性和有效的个体识别。这种全面的遗传表征为泰国家猫品种的保护策略和育种实践提供了宝贵的见解。
    Over hundreds of years, cats have been domesticated and selectively bred, resulting in numerous pedigreed breeds expedited by recent cat shows and breeding associations. Concerns have been raised about the limited breeding options and the genetic implications of inbreeding, indicating challenges in maintaining genetic diversity and accurate identification in purebred cats. In this study, genetic variability and structure were examined in 5 Thai domestic cat breeds using 15 microsatellite markers and mitochondrial DNA (mtDNA) D-loop sequencing. In total, 184 samples representing the Wichien Maat (WCM), Suphalak (SL), Khao-Manee (KM), Korat (KR), and Konja (KJ) breeds were analyzed. High genetic diversity (Ho and He > 0.5) was observed in all breeds, and mtDNA analysis revealed two primary haplogroups (A and B) that were shared among all domestic cat breeds in Thailand and globally. However, minor differences were observed between Thai domestic cat breeds based on clustering analyses, in which a distinct genetic structure was observed in the WCM breed. This suggests that allele fixation for distinctive morphological traits has occurred in Thai domestic cat breeds that emerged in isolated regions with shared racial origins. Analysis of relationships among individuals within the breed revealed high identification efficiency in Thai domestic cat breeds (P(ID)sibs < 10-4). Additionally, diverse and effective individual identification can be ensured by optimizing marker efficiency by using only nine loci. This comprehensive genetic characterization provides valuable insights into conservation strategies and breeding practices for Thai domestic cat breeds.
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  • 文章类型: Journal Article
    遗传多样性是成功入侵的重要生物学性状。在新领土扩张期间,入侵物种可能面临前所未有的生态条件,这将决定其人口和遗传多样性。黄腿大黄蜂(Vespavelutina)在欧洲的第一个记录可以追溯到2004年在法国,从那里它成功地传播到非洲大陆的大片领土,包括意大利,西班牙和葡萄牙。综合方法提供了一种强大的策略来检测和理解中央和边缘种群的遗传变异模式。这里,我们分析了从15V.velutina核DNA微卫星基因座推断的遗传多样性参数之间的关系,以及地理和环境驱动因素,比如到引言焦点的距离,环境适宜性和与原生和侵入性生态位质心的距离。我们的结果揭示了一个中央边缘动态,等位基因丰富度向扩展范围的边缘降低。边缘种群入侵的领土的低环境适应性可能会阻止多样化的种群在扩展边缘建立和减少种群的遗传多样性。此外,马尔可夫链蒙特卡罗分析显示,地理和环境距离都影响着种群的遗传分化。这项研究强调了将遗传分析与地理和环境驱动因素相结合的重要性,以了解入侵物种对新环境的遗传趋势。
    Genetic diversity is an important biological trait for a successful invasion. During the expansion across a new territory, an invasive species may face unprecedented ecological conditions that will determine its demography and genetic diversity. The first record of the yellow-legged hornet (Vespa velutina) in Europe dates back to 2004 in France, from where it has successfully spread through a large territory in the continent, including Italy, Spain and Portugal. Integrative approaches offer a powerful strategy to detect and understand patterns of genetic variation in central and marginal populations. Here, we have analysed the relationship between genetic diversity parameters inferred from 15 V. velutina nuclear DNA microsatellite loci, and geographical and environmental drivers, such as the distance to the introduction focus, environmental suitability and distance to native and invasive niche centroids. Our results revealed a central-marginal dynamic, where allelic richness decreased towards the edge of the expansion range. The low environmental suitability of the territories invaded by marginal populations could prevent a diverse population from establishing and reducing the genetic diversity in populations at the expansion edge. Moreover, Markov chain Monte Carlo analysis showed both geographical and environmental distances were influencing population genetic differentiation. This study highlights the importance of combining genetic analysis with geographical and environmental drivers to understand genetic trends of invasive species to new environment.
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  • 文章类型: Journal Article
    金子花是春季短命金子花属中亚热带地区唯一分布的物种。人类的广泛开发和栖息地的破坏导致了G.kiangnanense种群的迅速减少。本研究利用微卫星标记分析了江西现存种群的遗传多样性和结构,并推导了历史种群事件。
    共有来自8个现存G.kiangnanense种群的143个人,包括安徽省的两个人口和浙江省的六个人口,使用21对微卫星标记进行了分析。使用Cervus计算遗传多样性指数,GENEPOP,GenaLEX.利用遗传距离(UPGMA)评估种群结构,主坐标分析(PCoA),贝叶斯聚类方法(结构),和分子变异方差分析(AMOVA)。使用DIYABC推断种群历史事件。
    所研究的G.kiangnanense种群表现出低水平的遗传多样性(He=0.179,I=0.286),但遗传分化程度高(FST=0.521)。种群间基因流(Nm)的平均值为1.082,表明通过花粉扩散进行的基因交换普遍存在。系统地理学分析表明,江南菜的种群分为两个谱系,浙江(ZJ)和安徽(AH)。这两个谱系被黄山-天目山山脉隔开。AMOVA分析显示,总遗传变异的36.59%发生在两组之间。ZJ谱系进一步分为杭州(ZJH)和诸暨(ZJZ)谱系,被龙门山和富春河隔开。DIYABC分析表明,ZJ和AH谱系在5.592ka分离,可能是由于全新世气候变化和人类活动的影响。随后,ZJZ谱系在2.112ka左右与ZJH谱系不同。考虑到kiangnanense的有限分布及其谱系之间的显著遗传分化,应实施原位和异地保护策略,以保护G.kiangnanense的种质资源。
    UNASSIGNED: Gymnospermium kiangnanense is the only species distributed in the subtropical region within the spring ephemeral genus Gymnospermium. Extensive human exploitation and habitat destruction have resulted in a rapid shrink of G. kiangnanense populations. This study utilizes microsatellite markers to analyze the genetic diversity and structure and to deduce historical population events of extant populations of G. kiangnanense.
    UNASSIGNED: A total of 143 individuals from eight extant populations of G. kiangnanense, including two populations from Anhui Province and six populations from Zhejiang Province, were analyzed with using 21 pairs of microsatellite markers. Genetic diversity indices were calculated using Cervus, GENEPOP, GenALEX. Population structure was assessed using genetic distance (UPGMA), principal coordinate analysis (PCoA), Bayesian clustering method (STRUCTURE), and molecular variation analysis of variance (AMOVA). Population history events were inferred using DIYABC.
    UNASSIGNED: The studied populations of G. kiangnanense exhibited a low level of genetic diversity (He = 0.179, I = 0.286), but a high degree of genetic differentiation (FST = 0.521). The mean value of gene flow (Nm ) among populations was 1.082, indicating prevalent gene exchange via pollen dispersal. Phylogeographic analyses suggested that the populations of G. kiangnanense were divided into two lineages, Zhejiang (ZJ) and Anhui (AH). These two lineages were separated by the Huangshan-Tianmu Mountain Range. AMOVA analysis revealed that 36.59% of total genetic variation occurred between the two groups. The ZJ lineage was further divided into the Hangzhou (ZJH) and Zhuji (ZJZ) lineages, separated by the Longmen Mountain and Fuchun River. DIYABC analyses suggested that the ZJ and AH lineages were separated at 5.592 ka, likely due to the impact of Holocene climate change and human activities. Subsequently, the ZJZ lineage diverged from the ZJH lineage around 2.112 ka. Given the limited distribution of G. kiangnanense and the significant genetic differentiation among its lineages, both in-situ and ex-situ conservation strategies should be implemented to protect the germplasm resources of G. kiangnanense.
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  • 文章类型: Journal Article
    在这项工作中,我们分析了小麦的形态和遗传结构,T.capitatum及其杂种T.×rohlenae来自三个同位种群。形态计量学研究表明,亲本及其杂种表现出连续的形态变异,杂种恰好位于父母之间。遗传分析显示,在形态上鉴定为T.×rohlenae的植物是可育的杂种,产生以后代杂种为主的杂种群。这表明渗入,而不是物种形成,是这些植物物种之间杂交的更可能的结果。两个物种之间的基因流的程度和方向在三个同位位置之间显着不同。在Trilj地区,这显然是单向的,以T.Capetatum发挥主导作用。在西奇沃地区,基因流稍微不对称,有利于头花T.的遗传背景,而在Sliven现场,它在相反的方向上是完全不对称的。在Trilj地区观察到了单向基因流动的极端情况,在该地区,在形态上鉴定为T.montanum的植物无法在遗传上与T.capetatum区分开。这表明种间杂交发生在很久以前,导致渗入和神秘杂交,物种边界模糊并产生进化噪声。
    In this work, we analyzed the morphology and genetic structure of Teucrium montanum, T. capitatum and their hybrid T. × rohlenae from three syntopic populations. A morphometric study showed that the parents and their hybrids exhibited continuous morphological variation, with the hybrid positioned exactly between the parents. Genetic analysis revealed that plants morphologically identified as T. × rohlenae are fertile hybrids that produce hybrid swarms dominated by later-generation hybrids. This suggests that introgression, rather than speciation, is the more likely outcome of hybridization between these plant species. The extent and direction of gene flow between the two species differed markedly between the three syntopic localities. At the Trilj locality, it was clearly unidirectional, with T. capitatum playing the dominant role. At the Sićevo locality, gene flow was slightly asymmetric, favoring the genetic background of T. capitatum, while at the Sliven site, it was completely asymmetric in the opposite direction. The extreme case of unidirectional gene flow was observed at the Trilj locality where plants morphologically identified as T. montanum could not be genetically distinguished from T. capitatum. This suggests that interspecific hybridization occurred long ago, leading to introgression and cryptic hybrids, blurring of species boundaries and generating evolutionary noise.
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  • 文章类型: Journal Article
    这项研究是表征Rhodusuyekii基因组并研究微卫星标记及其应用于野生种群遗传结构的开发的第一份报告。基因组组装基于PacBioHiFi和IlluminaHiSeq配对末端测序,导致了R.uyekii的基因组组装草案。将草图基因组组装成2652个重叠群。组件的完整性评估表明草案组件的质量很高,Verbrata数据库中有3259个完整的BUSCOs(97.2%)。在蛋白质数据库中注释了总共31,166个预测的蛋白质编码基因。系统发育树显示,杜氏毛虫是巨毛甲虫的近亲但不同的亲戚。在10个鱼类基因组中,有显著的基因家族扩增(8-2387)和收缩(16-2886)。通过21个多态性标记扩增的等位基因的平均数量为6至23个,平均PIC值为0.753,这将对进化和遗传分析有用。利用群体遗传分析,我们分析了来自6个种群的120个个体的遗传多样性和遗传结构。每个群体的平均等位基因数在7.6到9.9之间,观察到的杂合性在0.496到0.642之间,预期杂合性在0.587到0.783之间。主成分的判别分析根据分析方法,人口分为三个群体(BS与DCvs.GG,GC,MS,DC)。总之,我们的研究为比较基因组学提供了有用的资源,系统发育,和未来的人口研究。
    This study is the first report to characterize the Rhodus uyekii genome and study the development of microsatellite markers and their markers applied to the genetic structure of the wild population. Genome assembly was based on PacBio HiFi and Illumina HiSeq paired-end sequencing, resulting in a draft genome assembly of R. uyekii. The draft genome was assembled into 2652 contigs. The integrity assessment of the assemblies indicates that the quality of the draft assemblies is high, with 3259 complete BUSCOs (97.2%) in the database of Verbrata. A total of 31,166 predicted protein-coding genes were annotated in the protein database. The phylogenetic tree showed that R. uyekii is a close but distinct relative of Onychostoma macrolepis. Among the 10 fish genomes, there were significant gene family expansions (8-2387) and contractions (16-2886). The average number of alleles amplified by the 21 polymorphic markers ranged from 6 to 23, and the average PIC value was 0.753, which will be useful for evolutionary and genetic analysis. Using population genetic analysis, we analyzed genetic diversity and the genetic structures of 120 individuals from 6 populations. The average number of alleles per population ranged from 7.6 to 9.9, observed heterozygosity ranged from 0.496 to 0.642, and expected heterozygosity ranged from 0.587 to 0.783. Discriminant analysis of principal components According to the analysis method, the population was divided into three populations (BS vs. DC vs. GG, GC, MS, DC). In conclusion, our study provides a useful resource for comparative genomics, phylogeny, and future population studies of R. uyekii.
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  • 文章类型: Editorial
    冷杉属广泛分布于世界各地,对林业具有重要意义。由于叶绿体通常是单亲遗传的,它们是解决基因流动等特定科学问题的重要工具,亲子关系,迁移和,总的来说,进化分析。在针叶树中建立的细胞器遗传标记相当限于RFLP标记,更多的劳动力和时间密集,与SSR标记相比。使用QUIAGENCLCWorkbench23.03,我们将来自不同冷杉物种的两个叶绿体基因组(NCBI种质:NC_039581,NC_042778,NC_039582,NC_042410,NC_035067,NC_062889,NC_042775,NC_057314,NC_041464,MH706244,MH047653潜在使用NCBI引物Blast服务器应用程序进行正向和反向引物的进一步选择和开发。在这篇文章中,我们为各种冷杉物种引入了一个非常多态的SSR标记集,这对其他针叶树属可能有用,比如Cedrus,松树,Pseudotsuga或Picea。总的来说,17个cpSSRs显示出可靠的扩增和多态性,总共检测到68个单倍型。在测试的冷杉属中扩增了所有17个cpSSR。在其他测试物种中,除了Taxusbaccata,至少一个引物是多态的。
    The genus Abies is widely distributed across the world and is of high importance for forestry. Since chloroplasts are usually uniparentally inherited, they are an important tool for specific scientific issues like gene flow, parentage, migration and, in general, evolutionary analysis. Established genetic markers for organelles in conifers are rather limited to RFLP markers, which are more labour and time intensive, compared with SSR markers. Using QUIAGEN CLC Workbench 23.03, we aligned two chloroplast genomes from different Abies species (NCBI accessions: NC_039581, NC_042778, NC_039582, NC_042410, NC_035067, NC_062889, NC_042775, NC_057314, NC_041464, MH706706, MH047653 and MH510244) to identify potential SSR candidates. Further selection and development of forward and reverse primers was performed using the NCBI Primer Blast Server application. In this article, we introduce a remarkably polymorphic SSR marker set for various Abies species, which can be useful for other conifer genera, such as Cedrus, Pinus, Pseudotsuga or Picea. In total, 17 cpSSRs showed reliable amplification and polymorphisms in A. grandis with a total of 68 haplotypes detected. All 17 cpSSRs amplified in the tested Abies spp. In the other tested species, except for Taxus baccata, at least one primer was polymorphic.
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  • 文章类型: Journal Article
    背景:串联重复是基因组DNA中串联重复的特定序列,存在于所有生物体中。在TR的子类别中,我们有卫星重复,它分为宏观卫星,小型卫星,和微型卫星,是最后两个特别感兴趣的,因为它们可以由于生物体的不稳定性而识别生物体之间的多态性。目前,大多数挖掘工具专注于简单序列重复(SSR)挖掘,只有少数可以识别编码区的SSR。
    结果:我们基于用C和Python编写的新滑动窗口算法,开发了一种名为SATIN(Micro和MiniSATelliteIdentifatioN工具)的微卫星采矿软件。通过解决现有工具的局限性,它代表了一种新的SSR挖掘方法,特别是在编码区SSR挖掘中。SATIN可在https://github.com/labgm/SATIN获得。git.它被证明是完美和复合SSR采矿的第二快。它可以识别来自编码区的SSR加上基序大小大于6的SSR。除了SSR采矿,SATIN还可以分析来自预定组的编码区的SSRs多态性,并在每个基因的基础上鉴定它们之间差异丰富的SSR。要验证,我们分析了来自两组大肠杆菌(K12和O157)的SSR,并将结果与来自编码区的5个已知SSR进行了比较。SATIN从237个基因中鉴定出所有5个SSR,其中至少有一个SSR。
    结论:SATIN是一种新颖的微卫星搜索软件,它利用基于数字列表的创新滑动窗口技术进行重复区域搜索,以识别完美的,和复合SSR,同时产生可理解和可分析的输出。它是一种能够使用fasta或GenBank格式的文件作为微型卫星采矿的输入的工具,还能够识别GenBank文件的编码区中存在的SSR。总之,我们希望SATIN能够帮助识别潜在的SSR用作遗传标记。
    BACKGROUND: Tandem repeats are specific sequences in genomic DNA repeated in tandem that are present in all organisms. Among the subcategories of TRs we have Satellite repeats, that is divided into macrosatellites, minisatellites, and microsatellites, being the last two of specific interest because they can identify polymorphisms between organisms due to their instability. Currently, most mining tools focus on Simple Sequence Repeats (SSR) mining, and only a few can identify SSRs in the coding regions.
    RESULTS: We developed a microsatellite mining software called SATIN (Micro and Mini SATellite IdentificatioN tool) based on a new sliding window algorithm written in C and Python. It represents a new approach to SSR mining by addressing the limitations of existing tools, particularly in coding region SSR mining. SATIN is available at https://github.com/labgm/SATIN.git . It was shown to be the second fastest for perfect and compound SSR mining. It can identify SSRs from coding regions plus SSRs with motif sizes bigger than 6. Besides the SSR mining, SATIN can also analyze SSRs polymorphism on coding-regions from pre-determined groups, and identify SSRs differentially abundant among them on a per-gene basis. To validate, we analyzed SSRs from two groups of Escherichia coli (K12 and O157) and compared the results with 5 known SSRs from coding regions. SATIN identified all 5 SSRs from 237 genes with at least one SSR on it.
    CONCLUSIONS: The SATIN is a novel microsatellite search software that utilizes an innovative sliding window technique based on a numerical list for repeat region search to identify perfect, and composite SSRs while generating comprehensible and analyzable outputs. It is a tool capable of using files in fasta or GenBank format as input for microsatellite mining, also being able to identify SSRs present in coding regions for GenBank files. In conclusion, we expect SATIN to help identify potential SSRs to be used as genetic markers.
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  • 文章类型: Journal Article
    微卫星,称为简单序列重复(SSR),是在所有基因组中发现的1到6个核苷酸基序的短串联重复,尤其是真核生物。它们被广泛用作遗传分析和分子育种中的共显性标记。小麦,一个部落的草,包括主要的谷类作物,如面包小麦,大麦,还有黑麦,以及丰富的牧草和草坪草,在全球粮食生产和农业中发挥着至关重要的作用。为了加强遗传工作,加快小麦作物的改良,我们开发了TriticeaeSSRdb,一个集成和用户友好的数据库。它包含来自21个物种的3,891,705个SSR,并提供基于基因组区域的浏览选项,染色体,主题类型,和重复基序序列。高级搜索功能允许基于SSR的染色体位置和长度的个性化搜索。用户还可以探索与SSR相关的基因,设计用于PCR验证的定制引物对,并利用实用工具进行全基因组浏览,序列比对,以及从局部序列进行计算机SSR预测。我们不断更新TriticeaeSSRdb与其他物种和实用工具。我们预计该数据库将极大地促进小麦作物的性状遗传分析并增强分子育种策略。研究人员可以自由访问数据库http://triticeaessrdb.com/。
    Microsatellites, known as simple sequence repeats (SSRs), are short tandem repeats of 1 to 6 nucleotide motifs found in all genomes, particularly eukaryotes. They are widely used as co-dominant markers in genetic analyses and molecular breeding. Triticeae, a tribe of grasses, includes major cereal crops such as bread wheat, barley, and rye, as well as abundant forage and lawn grasses, playing a crucial role in global food production and agriculture. To enhance genetic work and expedite the improvement of Triticeae crops, we have developed TriticeaeSSRdb, an integrated and user-friendly database. It contains 3,891,705 SSRs from 21 species and offers browsing options based on genomic regions, chromosomes, motif types, and repeat motif sequences. Advanced search functions allow personalized searches based on chromosome location and length of SSR. Users can also explore the genes associated with SSRs, design customized primer pairs for PCR validation, and utilize practical tools for whole-genome browsing, sequence alignment, and in silico SSR prediction from local sequences. We continually update TriticeaeSSRdb with additional species and practical utilities. We anticipate that this database will greatly facilitate trait genetic analyses and enhance molecular breeding strategies for Triticeae crops. Researchers can freely access the database at http://triticeaessrdb.com/.
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  • 文章类型: Journal Article
    细胞因子巨噬细胞迁移抑制因子(MIF)基因的功能变体由4个核苷酸的启动子微卫星(-794CATT5-8,rs5844572)定义,并赋予自身免疫性风险,传染性,和肿瘤疾病。我们在这里描述了原型的发现,MIF转录的小分子抑制剂,具有高微卫星重复数的选择性和相应的高基因表达。利用高通量发光接近屏,我们鉴定了1-碳甲氧基-5-甲酰基-4,6,8-三羟基吩嗪(CMFT)以抑制转录因子ICBP90(也称为UHRF1)和MIF-794CATT5-8启动子微卫星之间的功能相互作用。CMFT以-794CATT5-8长度依赖性方式抑制MIFmRNA表达,IC50为470nM,并优先降低高基因型与低基因型MIF表达巨噬细胞中ICBP90依赖性MIFmRNA和蛋白质的表达。RNA表达分析还显示CMFT下调MIF依赖性,炎症基因表达,很少有脱靶代谢毒性的证据。这些发现为推进基于精确的MIF抑制剂用于多种自身免疫和炎性病症的药物基因组开发提供了概念验证。
    Functional variants of the gene for the cytokine macrophage migration inhibitory factor (MIF) are defined by a 4-nucleotide promoter microsatellite (-794 CATT5-8, rs5844572) and confer risk for autoimmune, infectious, and oncologic diseases. We describe herein the discovery of a prototypic, small molecule inhibitor of MIF transcription with selectivity for high microsatellite repeat number and correspondingly high gene expression. Utilizing a high-throughput luminescent proximity screen, we identify 1-carbomethoxy-5-formyl-4,6,8-trihydroxyphenazine (CMFT) to inhibit the functional interaction between the transcription factor ICBP90 (namely, UHRF1) and the MIF -794 CATT5-8 promoter microsatellite. CMFT inhibits MIF mRNA expression in a -794 CATT5-8 length-dependent manner with an IC50 of 470 nM, and preferentially reduces ICBP90-dependent MIF mRNA and protein expression in high-genotypic versus low-genotypic MIF-expressing macrophages. RNA expression analysis also showed CMFT to downregulate MIF-dependent, inflammatory gene expression with little evidence of off-target metabolic toxicity. These findings provide proof-of-concept for advancing the pharmacogenomic development of precision-based MIF inhibitors for diverse autoimmune and inflammatory conditions.
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