Systems Biology Analysis of Human Erythropoiesis

人类红细胞生成的系统生物学分析

• 批准号: 9294127
• 负责人: STUART H ORKIN
• 金额: $ 67.58万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9294127
• 关键词: Adult; Alleles; Area; Automobile Driving; Binding; Bioinformatics; Biological Models; Biological Process; Biology; Cell Differentiation process; Cell Maintenance; Chromatin; Collaborations; Computer Analysis; Computer Simulation; Computing Methodologies; Data; Data Set; Development; Developmental Gene; Developmental Process; Disease; Distal; Enhancers; Erythrocytes; Erythroid; Erythroid Progenitor Cells; Erythropoiesis; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic Enhancer Element; Genetic Transcription; Genomics; Genotype; Hematological Disease; Human; Investigation; Life; Link; Mammals; Mediating; Methods; Modeling; Molecular; Molecular Genetics; Organ; Oxygen; Play; Process; Production; Regulation; Regulator Genes; Regulatory Element; Research; Role; Specificity; System; Systems Biology; Tissues; Variant; Vertebrates; Work; cell type; cofactor; combinatorial; cost; epigenomics; experience; experimental study; fetal; genetic variant; genome wide association study; genome-wide; genomic data; human data; human subject; improved; insight; network models; programs; public health relevance; response; trait; transcription factor; transcriptome; transcriptomics

DESCRIPTION (provided by applicant): Erythropoiesis is a fundamental process in vertebrate animals and has long served as a paradigm for molecular investigations of developmental regulation. It has been well established that a small number of transcription factors, also known as master regulators, play an essential role in the maintenance of cell-identity and/or regulate the cell differentiation process. However, it is not fully elucidated how they work in combination with each other or various cofactors, particularly at different developmental stages. Since there are at least a thousand transcriptional regulators in mammals, the number of possible combinations is astronomical. Using experimental methods alone to dissect such complexity remains a daunting task as it demands prohibitively high cost and labor. To overcome this challenge, we propose a systems biology approach to be carried out by a team of experienced experimental and computational biologists. Using human primary erythroid precursor cells as the model system, we will generate extensive experimental data by genomic, epigenomic, and transcriptomic profiling, develop data-integrative and predictive computational methods, and perturb the systems by disrupting the normal regulatory activities. Our preliminary work has identified important regulatory network differences between adult and fetal erythroid precursors and suggested that collaboration between master regulators and cofactors plays an important role in driving developmental stage-specific transcriptional changes through acting upon enhancer elements. This will be extended by focusing on the following specific aims: (1) Predict and validate the developmental stage-specific gene regulatory networks in human primary erythroid precursors by integrating genomic and epigenomic data-types; (2) Perturb the gene regulatory networks using molecular and genetic experiments and further integrate such information to refine our network model; (3) Characterize the role of genetic variants influencing chromatin state, gene expression, and erythroid traits. In the end our results will greatly expand our current mechanistic understanding of combinatorial control in establishing cell-type and developmental stage-specificity and provide functional insights into erythroid trait- associated genetic variants.

描述（由申请人提供）：红细胞生成是脊椎动物动物的一个基本过程，长期以来一直是用于发育调节分子​​研究的范式。已经确定的是，少数转录因子（也称为主调节剂）在维持细胞认同和/或调节细胞分化过程中起着至关重要的作用。但是，尚未完全阐明它们如何相互结合或各种辅助因子，尤其是在不同的发育阶段。由于哺乳动物中至少有一千个转录调节剂，因此可能的组合数量是天文学的。仅使用实验方法来剖析这种复杂性仍然是一项艰巨的任务，因为它需要高昂的成本和劳动力。为了克服这一挑战，我们提出了一种系统生物学方法，由经验丰富的实验和计算生物学家团队进行。使用人类原发性红细胞前体细胞作为模型系统，我们将通过基因组，表观基因组和转录组分析生成广泛的实验数据，开发数据集成和预测的计算方法，并通过破坏正常调节活性来扰动系统。我们的初步工作已经确定了成人和胎儿红细胞前体之间的重要调节网络差异，并表明主调节器和辅助因子之间的协作在推动发育阶段特定的转录变化方面通过对增强子元素作用而发挥着重要作用。这将通过关注以下特定目的来扩展：（1）通过整合基因组和表观基因组数据类型来预测和验证人类原发性红细胞前体中特定阶段特异性基因调节网络； （2）使用分子和遗传实验的基因调节网络扰动基因调节网络，并进一步整合此类信息以完善我们的网络模型； （3）表征影响染色质状态，基因表达和红细胞性状的遗传变异的作用。最后，我们的结果将大大扩展我们对组合控制的当前机械理解，以建立细胞类型和发育阶段特异性，并为红细胞性状性状与遗传变异物提供功能见解。