Multiscale functional characterization of genomic variation in human developmental disorders

人类发育障碍基因组变异的多尺度功能表征

基本信息

  • 批准号:
    10689051
  • 负责人:
  • 金额:
    $ 195.93万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-01 至 2026-05-31
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract Large-scale studies have identified thousands of genetic variants linked to developmental defects, together with the regulatory elements harboring these variants and the cell types in which these variants likely function. This diversity of variants, regulatory elements, and cell types indicates that multiple mechanisms contribute to developmental defects. One key challenge to our understanding of these mechanisms is that the molecular, cellular, and functional phenotypes of each variant remain largely uncharacterized. Until these critical gaps in knowledge are addressed, the underlying molecular and cellular determinants of developmental disease susceptibility will remain incomplete. To bridge these gaps, we propose to establish the “UT Southwestern Center for Regulatory Element Variation and Function”. The primary goal of this Center is to systematically catalog molecular and cellular phenotypes for disease-associated enhancers in human development, with a focus on gaining insights into mechanisms of non-canonical human genetics and gene regulation. To build a generalizable framework to understanding the impact of human genetic variation on function, we propose a high throughput perturbation platform with three primary goals: (1) Contribute to a variant/element/phenotype catalog with relevance to diseases of human development, focusing on elements genetically associated with congenital heart disease (cardiomyocytes), autism (neurons), and placental defects (trophoblasts); (2) Contribute to a variant/element/phenotype catalog for non-canonical human genetics, focusing on two understudied topics in human genetics: pleiotropic effects and non-cell autonomous effects; and (3) Contribute to a variant/element/phenotype catalog with relevance to mechanisms of gene regulation, focusing on enhancer RNAs. The Center will take advantage of recent technological innovations in genome engineering, single-cell genomics, and high content screening to enable the multiscale functional characterization of genomic variation in human developmental disorders. Several of these techniques have been pioneered by investigators contributing to this project, including: the development of novel tools for enhancer perturbation and the coupling of endogenous enhancer perturbations with a single-cell RNA-Seq readout (Mosaic-Seq). Impact and Significance: The efforts on this project will lead to a number of key outcomes and deliverables, including (1) greater understanding of the relationships between sequence variation and genome function, (2) an extensive variant/element/phenotype catalog for the community, (3) tools for generating predictive models for the community, and (4) resources to enable future functional genomics studies. Together, our multifaceted and combinatorial approaches will open new horizons to understanding the impact of regulatory variants on developmental disease phenotypes.
项目总结/摘要 大规模的研究已经确定了数千种与发育缺陷有关的遗传变异, 以及携带这些变体的调节元件和这些变体可能在其中发生的细胞类型 功能变异体、调控元件和细胞类型的多样性表明, 导致发育缺陷。对我们理解这些机制的一个关键挑战是, 每种变异体的分子、细胞和功能表型仍基本上未被表征。直到这些关键的 知识的空白得到解决,发育性疾病的潜在分子和细胞决定因素 敏感性将保持不完整。为了弥合这些差距,我们建议建立“UT西南 监管要素变化和功能中心。该中心的主要目标是系统地 人类发育中疾病相关增强子的分子和细胞表型目录, 专注于深入了解非经典人类遗传学和基因调控的机制。 为了建立一个可推广的框架来理解人类遗传变异对功能的影响, 我们提出了一个高吞吐量扰动平台,其主要目标有三个:(1)有助于 与人类发育疾病相关的变异/元件/表型目录,重点是元件 与先天性心脏病(心肌细胞)、自闭症(神经元)和胎盘缺陷有遗传相关性 (滋养层);(2)有助于非规范人类遗传学的变体/元件/表型目录, 专注于人类遗传学中两个未充分研究的主题:多效性效应和非细胞自主效应; (3)有助于与基因调控机制相关的变体/元件/表型目录,重点是 增强子RNA该中心将利用基因组工程方面的最新技术创新, 单细胞基因组学和高含量筛选,以实现基因组的多尺度功能表征 人类发育障碍的变异。这些技术中有几种是由调查人员开创的 为该项目做出贡献,包括:开发用于增强子扰动和耦合的新工具 内源性增强子扰动与单细胞RNA-Seq读数(Mosaic-Seq)。 影响和意义:该项目的努力将产生一些关键成果, 可交付成果,包括(1)更好地理解序列变异和基因组之间的关系 功能,(2)社区的广泛变体/元件/表型目录,(3)生成 社区的预测模型,和(4)资源,使未来的功能基因组学研究。我们一起努力, 我们的多方面和组合的方法将打开新的视野,了解监管的影响, 发育疾病表型的变异。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Single-Cell Genomics: Catalyst for Cell Fate Engineering.
Computational identification of clonal cells in single-cell CRISPR screens.
  • DOI:
    10.1186/s12864-022-08359-1
  • 发表时间:
    2022-02-15
  • 期刊:
  • 影响因子:
    4.4
  • 作者:
    Wang Y;Xie S;Armendariz D;Hon GC
  • 通讯作者:
    Hon GC
Breaking enhancers to gain insights into developmental defects.
  • DOI:
    10.7554/elife.88187
  • 发表时间:
    2023-07-27
  • 期刊:
  • 影响因子:
    7.7
  • 作者:
    Armendariz DA;Sundarrajan A;Hon GC
  • 通讯作者:
    Hon GC
Enhancer regulatory networks globally connect non-coding breast cancer loci to cancer genes.
增强子调控网络在全球范围内将非编码乳腺癌基因座与癌症基因连接起来。
  • DOI:
    10.1101/2023.11.20.567880
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Wang,Yihan;Armendariz,Daniel;Wang,Lei;Zhao,Huan;Xie,Shiqi;Hon,GaryC
  • 通讯作者:
    Hon,GaryC
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Gary Chung Hon其他文献

Gary Chung Hon的其他文献

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{{ truncateString('Gary Chung Hon', 18)}}的其他基金

Systematic Assessment of Combinatorial Transcription Factor Activity
组合转录因子活性的系统评估
  • 批准号:
    10897439
  • 财政年份:
    2023
  • 资助金额:
    $ 195.93万
  • 项目类别:
Determinants of Cell State Reprogramming
细胞状态重编程的决定因素
  • 批准号:
    10626919
  • 财政年份:
    2022
  • 资助金额:
    $ 195.93万
  • 项目类别:
Determinants of Cell State Reprogramming
细胞状态重编程的决定因素
  • 批准号:
    10406224
  • 财政年份:
    2022
  • 资助金额:
    $ 195.93万
  • 项目类别:
Multiscale functional characterization of genomic variation in human developmental disorders
人类发育障碍基因组变异的多尺度功能表征
  • 批准号:
    10296634
  • 财政年份:
    2021
  • 资助金额:
    $ 195.93万
  • 项目类别:
Multiscale functional characterization of genomic variation in human developmental disorders
人类发育障碍基因组变异的多尺度功能表征
  • 批准号:
    10473897
  • 财政年份:
    2021
  • 资助金额:
    $ 195.93万
  • 项目类别:
Combinatorial Biology of Gene Regulation for Cellular Engineering
细胞工程基因调控的组合生物学
  • 批准号:
    10372278
  • 财政年份:
    2017
  • 资助金额:
    $ 195.93万
  • 项目类别:
Combinatorial Biology of Gene Regulation for Cellular Engineering
细胞工程基因调控的组合生物学
  • 批准号:
    9349247
  • 财政年份:
    2017
  • 资助金额:
    $ 195.93万
  • 项目类别:

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