Regulatory Mechanisms of CD4+ T Cell Differentiation

CD4 T细胞分化的调控机制

• 批准号: 10240966
• 负责人: GREGORY E CRAWFORD
• 金额: $ 98.48万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-30 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240966
• 关键词: A549; Administrative Supplement; Biological Assay; Biomedical Research; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Communities; Computer software; Data; Data Set; Elements; Feedback; Funding; Future; Gene Expression; Gene Expression Regulation; Gene Targeting; Generations; Genes; Genomics; Glucocorticoids; Goals; Helper-Inducer T-Lymphocyte; Human; Joints; K-562; Lead; Leadership; Mainstreaming; Manuscripts; Maps; Measures; Metadata; Methods; Modeling; Mus; National Human Genome Research Institute; Outcome; Plasmids; Population; Positioning Attribute; Process; Production; Protocols documentation; Publishing; Reagent; Recommendation; Regulatory Element; Regulatory T-Lymphocyte; Research; Research Activity; Resource Sharing; Resources; Strategic Planning; System; T cell differentiation; T-Lymphocyte; Technology; Work; comparative; experimental analysis; new technology; online resource; response; single cell sequencing; success; synergism; working group

Our ENCODE proposal aims to functionally characterize changes in gene regulation during the differentiation of mouse CD4+ T cells. We have already accomplished major primary goals of identifying regulatory elements that change activity during cell differentiation, and identifying regulatory elements that are sufficient to drive cell differentiation. We also have ongoing Year 4 studies to achieve our Aim of measuring effects of above-described regulatory elements on changes in gene expression during cell differentiation. Finally, we have completed several cross-ENCODE coordinated studies of human K562 and WTC-11 cells as part of the coordinated functional characterization center effort, and are now contributing to the comparative analysis of those results. We have five objectives of this request for an extension of funding. First, we plan to make highly efficient use of the experimental systems we have established to date to characterize gene targets of regulatory elements involved in CD4 T cell differentiation. Second, we will continue our teams leadership in comparing results from different functional characterization assays across the ENCODE consortium. Third, we will expand coordinated functional characterization efforts to include study of the genomic response to glucocorticoids. Glucocorticoid responses have been studied by ENCODE since 2008, and including functional characterization studies of the system at the conclusion of ENCODE will create new synergies with those previous data production efforts. We also view the theme of studying differential regulatory element activity as particularly important because the elements identified and the methods used are distinct from steady-state studies; and thus comparative analyses of how functional characterization technologies perform when assaying differential regulatory effects will be invaluable for guiding the future environmental response and perturbation studies. Fourth, we commit to submitting all data generated to the ENCODE DCC. Fifth, we also commit to distributing all reagents, protocols and results from comparative analyses for community use. The expected outcome of this extension of funding will be to substantially enhance the utility of ENCODE to inform future genomics research, particularly that involving high-throughput functional characterization assays and/or that involving environmental responses. That outcome aligns with recommendations by the ECP to enhance ENCODE studies of environmental response systems and to enhance coordination between data production and functional characterization centers. Those outcomes will be particularly impactful in the legacy of ENCODE as the NHGRI moves broadly to increase emphasis on studies of environmental responses and genomic perturbations as part of the 2020 Strategic Plan.

我们的ENCODE建议旨在从功能上表征基因调控在 小鼠CD4+T细胞的分化。我们已经实现了确定以下目标的主要主要目标 在细胞分化过程中改变活动的调节元件，并识别调节元件 足以驱动细胞分化的物质。我们也正在进行第四年的学习，以实现我们的目标 检测上述调控元件对细胞内基因表达变化的影响 差异化。最后，我们完成了对人类K562的几项交叉编码协调研究 和WTC-11细胞作为协调功能表征中心工作的一部分，现在 有助于对这些结果进行比较分析。我们在此请求中有五个目标 延长拨款期限。首先，我们计划高效利用我们已有的实验系统 迄今已建立用于表征与CD4T细胞有关的调节元件的基因靶点 差异化。第二，我们将继续领导我们的团队比较不同的结果 在整个ENCODE联盟中进行功能特性分析。三是协同拓展。 功能鉴定工作，包括研究基因组对糖皮质激素的反应。 自2008年以来，ENCODE一直在研究糖皮质激素的反应，包括功能性的 在Encode会议结束时对该系统的表征研究将产生新的协同效应 那些之前的数据生产努力。我们也看到了研究差别监管的主题 元素活动特别重要，因为确定的元素和使用的方法是 不同于稳态研究；从而比较分析功能特性如何 技术在分析不同监管效果时的表现将对指导 未来的环境响应和扰动研究。第四，我们承诺提交所有数据 生成到ENCODE DCC。第五，我们还承诺分发所有试剂、方案和结果 来自对社区使用的比较分析。这一资金延期的预期结果将是 将大大增强ENCODE的效用，为未来的基因组学研究提供信息，特别是 涉及高通量功能表征分析和/或涉及环境 回应。这一结果与ECP关于加强以下方面的编码研究的建议一致 环境响应系统，并加强数据编制和职能部门之间的协调 表征中心。这些结果将对ENCODE的遗产产生特别的影响，因为 NHGRI广泛采取行动，加大对环境响应和基因组研究的重视 作为2020年战略计划的一部分的扰动。

项目成果

Mechanosensitive genomic enhancers potentiate the cellular response to matrix stiffness.

机械敏感基因组增强剂增强细胞对基质刚度的反应。

• DOI: 10.1101/2024.01.10.574997
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Cosgrove,BrianD;Bounds,LexiR;Taylor,CarsonKey;Su,AlanL;Rizzo,AnthonyJ;Barrera,Alejandro;Crawford,GregoryE;Hoffman,BrentonD;Gersbach,CharlesA
• 通讯作者: Gersbach,CharlesA

Correcting signal biases and detecting regulatory elements in STARR-seq data.

• DOI: 10.1101/gr.269209.120
• 发表时间: 2021-05
• 期刊: Genome research
• 影响因子: 7
• 作者: Kim YS;Johnson GD;Seo J;Barrera A;Cowart TN;Majoros WH;Ochoa A;Allen AS;Reddy TE
• 通讯作者: Reddy TE