Multi-omics functional analysis of non-coding regulatory genome for genomic medicine

基因组医学非编码调控基因组的多组学功能分析

• 批准号: 10652385
• 负责人: Yarui Diao
• 金额: $ 46.05万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652385
• 关键词: Amino Acid Sequence; Biochemical; Biological Process; Biology; Cells; Chromatin; Code; DNA Sequence; Development; Disease; Disease model; Engineering; Enhancers; Epigenetic Process; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Genomic DNA; Genomic medicine; Genomics; Goals; Human Genome; Knowledge; Mediating; Modification; Molecular Analysis; Play; Proteins; RNA; RNA Sequences; Regulation; Research; Role; Testing; Therapeutic; Untranslated RNA; Work; human disease; in vivo Model; innovation; mouse model; multiple omics; novel strategies; recruit

ABSTRACT Less than 2% of the human genome sequences are protein-coding genes. It has been shown that at least 80% of the non-coding sequences of human genome are associated with certain chromatin biochemical modifications, and more than 70% of the genomic DNA can be transcribed into RNAs at various stages during development. Accumulating evidence suggests that these non-coding regulatory sequences are critical for spatial and temporal gene expression control. However, it remains challenging to determine whether and how these non-coding regulatory DNA and RNA sequences play a causal in a variety biological processes including diseases. In particular, questions of how the activity of enhancers are precisely controlled, and how non-coding RNAs recruit effector proteins to control gene expression and genome function, are largely unexplored. My overall hypothesis is that, cells integrate effector proteins and regulatory non-coding DNA and RNA sequences to create a spectrum of functionalities for precise gene regulation control. The rules governing these functionalities can then be derived by defining the key components, and examining how each functions alone and in combination. To test this, we have developed a robust, innovative multi-omics approaches allowing for comprehensive analysis of the molecular composition associated with non-coding DNA and RNA sequences. My long-term goal is to develop a predictive and functional understanding of the non-coding genome, which will elucidate how these regions can be specifically targeted for genomic medicine. Toward this goal, we seek to achieve three major goals: 1) Control enhancer activity through systematic and targeted recruitment of epigenetic effectors; 2) Define the regulome of lncRNA-mediated gene regulation; 3). Develop innovative mouse model to study the function and regulation of non-coding genome disease model in vivo. Our work will have a broad impact to advance genomics research and genomics medicine by developing new approaches and new mouse models to deepen our knowledge on non-coding regulatory genome.

抽象的 不到 2% 的人类基因组序列是蛋白质编码基因。已经证明至少 人类基因组80%的非编码序列与某些染色质生化相关 修饰，超过70%的基因组DNA可以在各个阶段转录成RNA 在开发过程中。越来越多的证据表明这些非编码调控序列 对于空间和时间基因表达控制至关重要。然而，确定仍然具有挑战性 这些非编码调控 DNA 和 RNA 序列是否以及如何在多种生物中发挥因果作用 过程，包括疾病。特别是，增强子的活性如何精确地发挥作用的问题 控制，以及非编码 RNA 如何招募效应蛋白来控制基因表达和基因组 的功能，很大程度上尚未被探索。我的总体假设是，细胞整合效应蛋白和调节蛋白 非编码 DNA 和 RNA 序列可创建一系列用于精确基因调控的功能 控制。然后可以通过定义关键组件来导出管理这些功能的规则，并且 检查每个功能如何单独和组合发挥作用。为了测试这一点，我们开发了一个强大的、 创新的多组学方法可对分子组成进行全面分析 与非编码 DNA 和 RNA 序列相关。我的长期目标是开发一个预测性和 对非编码基因组的功能理解，这将阐明这些区域如何 专门针对基因组医学。为了实现这一目标，我们力求实现三个主要目标：1） 通过系统和有针对性地募集表观遗传效应子来控制增强子活性； 2) 定义 lncRNA介导的基因调控的调控组； 3）。开发创新的小鼠模型来研究功能 体内非编码基因组疾病模型的调控。我们的工作将对推进产生广泛影响 基因组学研究和基因组医学通过开发新方法和新小鼠模型来 加深我们对非编码调控基因组的了解。

项目成果

Maf family transcription factors are required for nutrient uptake in the mouse neonatal gut.

Maf 家族转录因子是小鼠新生肠道营养吸收所必需的。

• 发表时间: 2022-12-01
• 作者: Bara, Anne M;Chen, Lei;Ma, Celina;Underwood, Julie;Moreci, Rebecca S;Sumigray, Kaelyn;Sun, Tongyu;Diao, Yarui;Verzi, Michael;Lechler, Terry
• 通讯作者: Lechler, Terry

Crosstalk between RNA m6A and DNA methylation regulates transposable element chromatin activation and cell fate in human pluripotent stem cells.

RNA m6A 和 DNA 甲基化之间的串扰调节人类多能干细胞中转座元件染色质激活和细胞命运。

• 发表时间: 2023-08
• 影响因子: 30.8
• 作者: Sun, Tongyu;Xu, Yueyuan;Xiang, Yu;Ou, Jianhong;Soderblom, Erik J;Diao, Yarui
• 通讯作者: Diao, Yarui

HiCAR is a robust and sensitive method to analyze open-chromatin-associated genome organization.

HiCAR 是一种稳健且灵敏的方法，用于分析开放染色质相关的基因组组织。

• 发表时间: 2022-03-17
• 影响因子: 16
• 作者: Wei, Xiaolin;Xiang, Yu;Peters, Derek T;Marius, Choiselle;Sun, Tongyu;Shan, Ruocheng;Ou, Jianhong;Lin, Xin;Yue, Feng;Li, Wei;Southerland, Kevin W;Diao, Yarui
• 通讯作者: Diao, Yarui

analysis of chromatin accessibility and interactions with transcriptome by HiCAR 2

通过 HiCAR 2 分析染色质可及性以及与转录组的相互作用

• 发表时间: 2024-09-14
• 作者: Xiaolin Wei;Yu Xiang;Ruocheng Shan;Derek T. Peters;Tongyu Sun;Xin Lin;Wei Li;Yarui Diao
• 通讯作者: Yarui Diao

Skeletal muscle regeneration failure in ischemic-damaged limbs is associated with pro-inflammatory macrophages and premature differentiation of satellite cells.

缺血损伤肢体的骨骼肌再生失败与促炎巨噬细胞和卫星细胞过早分化有关。

• 发表时间: 2023-11-10
• 影响因子: 12.3
• 作者: Southerland, Kevin W;Xu, Yueyuan;Peters, Derek T;Lin, Xin;Wei, Xiaolin;Xiang, Yu;Fei, Kaileen;Olivere, Lindsey A;Morowitz, Jeremy M;Otto, James;Dai, Qunsheng;Kontos, Christopher D;Diao, Yarui
• 通讯作者: Diao, Yarui