Decoding transcriptional control in higher eukaryotes

解码高等真核生物的转录控制

• 批准号: 6549433
• 负责人: ERIC D. SIGGIA
• 金额: $ 16.7万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6549433
• 关键词: Drosophilidae; binding sites; computer program /software; eukaryote; gene expression; genetic transcription; glia; in situ hybridization; mathematical model; microarray technology; transcription factor

DESCRIPTION (provided by applicant):The regulation of gene transcription is crucial for the function and development of all organisms. While gene prediction programs that identify protein coding sequence have been used with remarkable success in the annotation of recently published genomes, the development of computational methods to analyse noncoding regions and delineate transcriptional control elements is still in its infancy. Using Drosophila melanogaster as a model, we intend to develop and validate computational strategies to locate the transcriptional control modules in the noncoding regions of the genome of higher eukaryotes where multiple inputs come together to control a gene in a particular context, and to parse them into individual transcription factor binding sites. Focusing on two transcriptional paradigms, the patterning of the early embryo by the segmentation genes and the specification of the glial cell fate by the master transcriptional regulator, Glial cells missing, we will develop algorithms that use raw genomic sequence and supplemental information such as the regulatory region of the orthologous gene in a related species, examples of transcription factor binding sites pertinent to a certain class of sequence modules, and one or more related sequence modules with unknown protein binding sites. All computational strategies will rely on probabilistic models of how the genome encodes regulatory information and will be built in part on algorithms we have developed for yeast. They will exploit the frequent occurance of multiple copies of the same binding motif in a module, and the enrichment of certain combinations of motifs in a module in comparison with the genome at large. The proposed research involves the close collaboration between a computational and an experimental group: In order to validate computational predictions in vivo, we will use reporter gene constructs to test putative regulatory modules, whole mount in situ hybridizations to determine whether a gene is expressed in a specific tissue, and DNA chips for genome-wide expression profiling; DNA chip data will also furnish raw input for further computational analysis. The results of the validation experiments will be used to refine and improve our algorithms. Finally, the analysis will be extended to other higher eukaryotic genomes, and the computational tools we develop will be made available to the scientific community at large.

描述（由申请人提供）：基因转录的调节对于所有生物体的功能和发育至关重要。虽然基因预测程序，确定蛋白质编码序列已被用于注释最近发表的基因组显着的成功，计算方法的发展，分析非编码区和描绘转录控制元件仍处于起步阶段。使用果蝇作为一个模型，我们打算开发和验证计算策略，以定位在高等真核生物的基因组的非编码区的转录控制模块，多个输入走到一起，以控制一个基因在一个特定的背景下，并解析到个人的转录因子结合位点。专注于两个转录范式，早期胚胎的模式化的分割基因和规范的神经胶质细胞的命运的主转录调节，神经胶质细胞失踪，我们将开发算法，使用原始基因组序列和补充信息，如调节区的orthopathy基因在相关物种，转录因子结合位点的实例涉及某类序列模块，以及一个或多个具有未知蛋白质结合位点的相关序列模块。所有的计算策略都将依赖于基因组如何编码调控信息的概率模型，并将部分建立在我们为酵母开发的算法上。他们将利用模块中相同结合基序的多个拷贝的频繁出现，以及与整个基因组相比模块中某些基序组合的富集。该研究涉及计算和实验组之间的密切合作：为了在体内验证计算预测，我们将使用报告基因构建体来测试推定的调控模块，整体原位杂交来确定基因是否在特定组织中表达，以及DNA芯片用于全基因组表达谱分析; DNA芯片数据还将为进一步的计算分析提供原始输入。验证实验的结果将用于改进和改进我们的算法。最后，分析将扩展到其他高等真核生物基因组，我们开发的计算工具将提供给广大科学界。

项目成果

Cross-species comparison significantly improves genome-wide prediction of cis-regulatory modules in Drosophila.

• DOI: 10.1186/1471-2105-5-129
• 发表时间: 2004-09-09
• 期刊: BMC bioinformatics
• 影响因子: 3
• 作者: Sinha S;Schroeder MD;Unnerstall U;Gaul U;Siggia ED
• 通讯作者: Siggia ED

Stubb: a program for discovery and analysis of cis-regulatory modules.

Stubb：用于发现和分析顺式调节模块的程序。

• DOI: 10.1093/nar/gkl224
• 发表时间: 2006-07-01
• 期刊: NUCLEIC ACIDS RESEARCH
• 影响因子: 14.9
• 作者: Sinha, Saurabh;Liang, Yupu;Siggia, Eric
• 通讯作者: Siggia, Eric

Transcriptional control in the segmentation gene network of Drosophila.

• DOI: 10.1371/journal.pbio.0020271
• 发表时间: 2004-09
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Schroeder MD;Pearce M;Fak J;Fan H;Unnerstall U;Emberly E;Rajewsky N;Siggia ED;Gaul U
• 通讯作者: Gaul U