Genomic and Functional Analyses of Regulatory Regions in Vertebrate Sequences
脊椎动物序列调节区域的基因组和功能分析
基本信息
- 批准号:8349998
- 负责人:
- 金额:$ 109.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectArchitectureAreaBerylliumBindingBinding SitesBioinformaticsBiologicalBiologyCategoriesCattleCharacteristicsCodeCommunitiesComputer softwareDNA MethylationDNA RepairDataDevelopmentDiseaseElementsEndometrial CarcinomaEndometrial NeoplasmsEnhancersEnvironmentEpigenetic ProcessEtiologyEventGene ExpressionGene Expression RegulationGenesGenetic PolymorphismGenetic RecombinationGenetic TranscriptionGenomeGenomicsGoalsGroupingHeadHumanHuman GenomeIndiumLiteratureMalignant NeoplasmsMalignant neoplasm of ovaryMapsMessenger RNAMethodsMethylationModelingModificationMutationNeoplasm MetastasisNormal CellNucleic Acid Regulatory SequencesOnline SystemsOvaryPathway interactionsPatternPrimatesProcessPromoter RegionsProteinsPublishingRNARNA SplicingRegulationRegulator GenesRegulatory ElementResearchResearch PersonnelResearch Project GrantsSamplingScienceSequence AnalysisTestingTranscriptTranscription Initiation SiteUntranslated RNAUterusVariantWorkYangcis acting elementexomefallsfunctional genomicsgene therapyhuman diseaseinsightinterestnovelovarian neoplasmpreventpromotertooltranscription factortumorvertebrate genome
项目摘要
Bidirectional promoters are abundant in the genome. They are defined as a shared regulatory region that falls in the intergenic space between two oppositely oriented genes that are separated by no more than 1,000 bp. These genes are organized in a head-to-head arrangement and transcribed away from one another. The closely spaced arrangement of the transcription start sites (TSSs) suggests that each pair of genes is recognized as a nonrandom event in the genome, proven by the fact that a greater than expected number of promoters have this architecture. One plausible scenario for the creation of bidirectional gene pairs is chromosomal recombination bringing the ends of two TSSs in close proximity. This union is likely to be irreversible because breakage of the intergenic promoter region would interrupt the normal regulation of two genes, profoundly affecting normal genomic function, such as DNA repair. We have mapped bidirectional promoters in numerous vertebrate genomes. In doing so, we are creating the first high-confidence regulatory map of bidirectional promoter sequences shared in vertebrate lineages as well as identifying transcripts that are unique to single vertebrate lineages, including primates. We have identified the first examples of lineage-specific transcripts in human and in cow using this approach. (Piontkivska H, Yang MQ, Larkin DM, Lewin HA, Reecy J, Elnitski L , BMC Genomics 2009 and Bovine Genome Consortium, including Elnitski L, Science 2009). In additon to bidirectional promoters we are investigating the specific activation of alternative promoters of genes and finding that their diverse and varied patterns have implications for understanding the etiology of diseases as well as the use of gene therapies (Jacox E, Gotea V, Ovcharenko I, Elnitski L PLoS One 2010).
In addition to characterizing promoter regions, we are interested in identifying novel types of elements such as negative regulators of gene expression (NREs; Petrykowska H, Vockley C, and Elnitski L, Genome Research 2008). In contrast to the large body of literature on positively acting elements such as enhancers and promoters, cis-acting NREs have not been extensively studied. Despite their scarceness in the literature, these elements are likely to be abundant in the genome. Examples of NREs include silencers, which decrease expression of a gene under their regulation and enhancer-blocking (EB) elements, which prevent the action of an enhancer on a promoter when placed between the two, but not otherwise. By developing a strategy to experimentally test NREs, we have identified novel examples of these functions in the human genome. This research provides the opportunity to test regions of the genome whose function is not known. Furthermore, as functional elements in the genome, silencers and enhancer-blockers are likely to be targets of mutations involved in human diseases. (ENCODE Consortium, PLoS Biol 2010).
Exonic splicing enhancers (ESEs) are a third category of regulatory elements affecting gene expression. We have compared all former predictive methods for ESEs to show that some approaches are more precise than others. We have produced an online toolkit to test polymorphisms that occur in coding sequences to assess whether they may affect mRNA splicing (http://research.nhgri.nih.gov/skippy). In addition to the web-based server, stand-alone software is available to the community for download. This software allows researchers to screen an unlimited number of variants of unknown function computationally, such as might be generated in whole exome sequencing analyses. (Woolfe A, Mullikin JC, and Elnitski L, Genome Biology 2010).
All of these research projects examine cis-acting elements and converge on the identification of transcription factor binding sites or splicing regulators, which are bound by trans-acting proteins and represent the basic components of gene regulation. Regulatory motifs have been published for each of the projects above. During the course of our work, novel motifs were implicated as silencers and new biological insights were revealed for the regulation of alternative promoters. A collaborative effort has been established to define the regulatory networks involving these motifs, especially in biological pathways implicated in cancer (Lichtenberg J, Kurz K, Liang X, Al-ouran R, Neiman L, Nau LJ, Welch JD, Jacox E, Bitterman T, Ecker K, Elnitski L, Drews F, Lee SS, Welch LR BMC Bioinformatics 2010).
Moreover, we are building tools to assess epigenetic events that aberrantly affect gene expression in tumors versus normal cells. Using an Illumina Infinium methylation array platform we have investigated the DNA methylation pattern in 36 ovarian tumors and an additional 12 normal samples. These are being compared to methylation patterns in endometrial tumors and metastatic tumors from the uterus to the ovary. In conjunction with DNA methylation, RNA-seq was performed on a large number of tumor and normal samples. The results identify loci with altered DNA methylation patterns whose transcript levels have also changed from the normal pattern. We are addressing the presence of specific mutations in these tumors which might connect the gene expression and DNA methylation patterns to a testable feature.
双向启动子在基因组中含量丰富。它们被定义为一个共同的调节区,位于两个相对定位的基因之间的基因间隙,两个基因之间的距离不超过1,000个碱基对。这些基因是以头对头的方式组织起来的,并相互转录。转录起始点(TSS)的紧密排列表明,每一对基因都被认为是基因组中的一个非随机事件,事实证明,比预期数量更多的启动子具有这种结构。创造双向基因对的一个看似合理的方案是染色体重组,使两个SSs的末端非常接近。这种结合很可能是不可逆转的,因为基因间启动子区域的破坏将扰乱两个基因的正常调节,深刻影响正常的基因组功能,如DNA修复。我们已经在许多脊椎动物基因组中定位了双向启动子。通过这样做,我们正在创建第一个在脊椎动物谱系中共享的双向启动子序列的高置信度调控图,并识别包括灵长类在内的单个脊椎动物谱系所独有的转录本。我们已经使用这种方法在人类和牛身上鉴定了第一个谱系特异性转录本的例子。(Piontkivska H,Yang MQ,Larkin DM,Lewin HA,Reecy J,Elnitski L,2009年BMC基因组和包括Elnitski L在内的牛基因组联盟,2009年)。除了双向启动子外,我们正在研究基因的替代启动子的特定激活,并发现它们的不同和不同的模式对于理解疾病的病因以及基因疗法的使用具有意义(Jacox E,GoTeA V,Ovcharenko I,Elnitski L PLoS One 2010)。
除了确定启动子区域的特征外,我们还对识别新类型的元件感兴趣,例如基因表达的负面调节(NRES;Petrykowska H,Vockley C和Elnitski L,基因组研究,2008年)。与大量关于促进剂和启动子等积极作用元件的文献相反,顺式作用的NRES还没有得到广泛的研究。尽管它们在文献中很稀少,但这些元素在基因组中很可能是丰富的。NRES的例子包括消音器和增强子阻断(EB)元件,前者在其调控下降低基因的表达,后者当被放置在两者之间时阻止增强子对启动子的作用,但不是在其他情况下。通过开发一种实验测试NRES的策略,我们已经在人类基因组中确定了这些功能的新例子。这项研究提供了测试基因组中功能未知的区域的机会。此外,作为基因组中的功能元件,沉默因子和增强子阻断因子很可能成为人类疾病相关突变的目标。(编码联盟,PLoS Biol 2010)。
外显子剪接增强子(ESES)是影响基因表达的第三类调控元件。我们比较了所有以前的ESES预测方法,以表明一些方法比另一些方法更精确。我们已经开发了一个在线工具包来测试编码序列中出现的多态,以评估它们是否会影响信使核糖核酸剪接(http://research.nhgri.nih.gov/skippy).除了基于Web的服务器外,社区还可以下载独立的软件。该软件允许研究人员在计算上筛选未知功能的无限数量的变体,例如可能在整个外显子组测序分析中产生的变体。(Woolfe A,Mullikin JC,和Elnitski L,基因组生物学,2010年)。
所有这些研究项目都在研究顺式作用元件,并集中在鉴定转录因子结合部位或剪接调节因子,它们与反式作用蛋白结合,代表基因调控的基本组成部分。已经为上述每个项目发布了监管主题。在我们的工作过程中,新的基序被认为是消音器,并为调节替代启动子提供了新的生物学见解。已经建立了一个协作努力来定义涉及这些基序的调控网络,特别是在与癌症有关的生物途径中(Lichtenberg J,Kurz K,Leung X,Al-Ouran R,Neiman L,NAU LJ,Welch JD,Jacox E,Bitterman T,Ecker K,Elnitski L,Drews F,Lee SS,Welch LR BMC BioInformation atics,2010年)。
此外,我们正在建立工具来评估表观遗传事件,这些事件对肿瘤中的基因表达产生异常影响,而不是正常细胞。利用Illumina Infinium甲基化阵列平台,我们研究了36例卵巢肿瘤和另外12例正常组织的DNA甲基化模式。这些都与子宫内膜肿瘤和从子宫到卵巢的转移肿瘤的甲基化模式进行了比较。在DNA甲基化的同时,对大量的肿瘤和正常样本进行了RNA-SEQ。结果确定了DNA甲基化模式发生变化的基因座,其转录水平也与正常模式发生了变化。我们正在解决这些肿瘤中存在的特定突变,这些突变可能会将基因表达和DNA甲基化模式与可测试的特征联系起来。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Laura L Elnitski其他文献
Laura L Elnitski的其他文献
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{{ truncateString('Laura L Elnitski', 18)}}的其他基金
Genomic Alignment to Detect Conserved Regulatory Regions
基因组比对检测保守调控区域
- 批准号:
6638077 - 财政年份:2001
- 资助金额:
$ 109.94万 - 项目类别:
Genomic Alignment to Detect Conserved Regulatory Regions
基因组比对检测保守调控区域
- 批准号:
6536491 - 财政年份:2001
- 资助金额:
$ 109.94万 - 项目类别:
Genomic Alignment to Detect Conserved Regulatory Regions
基因组比对检测保守调控区域
- 批准号:
6339476 - 财政年份:2001
- 资助金额:
$ 109.94万 - 项目类别:
Regulatory and epigenetic landscapes in biological discovery, diagnostics and disease mechanisms
生物发现、诊断和疾病机制中的调控和表观遗传学景观
- 批准号:
10700700 - 财政年份:
- 资助金额:
$ 109.94万 - 项目类别:
Genomic and Functional Analyses of Regulatory Regions in Vertebrate Sequences
脊椎动物序列调节区域的基因组和功能分析
- 批准号:
7968905 - 财政年份:
- 资助金额:
$ 109.94万 - 项目类别:
Genomic, Epigenetic and Functional Analyses of Vertebrate Regulatory Regions
脊椎动物调节区的基因组、表观遗传学和功能分析
- 批准号:
9152724 - 财政年份:
- 资助金额:
$ 109.94万 - 项目类别:
Genomic-Functional Analyses-Conserved Noncoding Regions
基因组功能分析保守的非编码区域
- 批准号:
7148000 - 财政年份:
- 资助金额:
$ 109.94万 - 项目类别:
Genomic and Functional Analyses of Conserved Noncoding Regions in Vertebrates
脊椎动物保守非编码区域的基因组和功能分析
- 批准号:
7734894 - 财政年份:
- 资助金额:
$ 109.94万 - 项目类别:
Regulatory and epigenetic landscapes in biological discovery, diagnostics and disease mechanisms
生物发现、诊断和疾病机制中的调控和表观遗传学景观
- 批准号:
10267094 - 财政年份:
- 资助金额:
$ 109.94万 - 项目类别:
Genomic and Functional Analyses of Regulatory Regions in Vertebrate Sequences
脊椎动物序列调节区域的基因组和功能分析
- 批准号:
8149435 - 财政年份:
- 资助金额:
$ 109.94万 - 项目类别:
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