Programmable control over histone acetylation at human regulatory elements using precision epigenome editing

使用精确表观基因组编辑对人类调控元件的组蛋白乙酰化进行可编程控制

基本信息

  • 批准号:
    10669331
  • 负责人:
  • 金额:
    $ 56.88万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-01 至 2024-02-29
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT Dysregulated gene expression contributes to nearly every human disease. The level at which we understand the inherent complexity of gene regulation ultimately dictates our ability to link and/or manipulate biomolecular changes and pathology. Beyond their function as a structural substrate, histone proteins play key roles in gene expression by selectively gating access to DNA and thereby guiding when and how transcriptional machinery engages the human genome. Histone-based gene regulatory control largely stems from post-translational modifications (PTMs) to histone proteins themselves. One type of PTM, histone lysine acetylation, is particularly critical for gene regulation and human health, because overall acetylation levels tightly correlate with genomic activity and gene expression, and inappropriate histone acetylation patterns are linked to diverse human diseases. In fact, small molecules that globally change histone acetylation across the human genome have emerged as important therapeutics. However, in many patients these drugs can be ineffective and/or can result in toxic side effects. Furthermore, small molecules that globally alter histone acetylation patterns cannot be used to dissect how changes at specific locations in the human genome drive disease pathology. Robust tools that enable precise and targeted control over endogenous histone acetylation are urgently needed, because these technologies could illuminate the function(s) that this complex epigenomic signature plays within the human genome and open the door to new sophisticated epigenetic therapies. In this project, we will fulfill this urgent need by building synthetic and precisely targetable biomolecules that mimic the spectrum of activities displayed by natural human histone acetyltransferases (HATs) and histone deacetylases (HDACs) (Aim 1). Specifically, we will combine the programmability of the nuclease null CRISPR/Cas9 (dCas9) scaffold with different classes of human HATs/HDACs and we will use these technologies to probe the selectivity of different HATs/HDACs in vitro and within native human chromatin. We will integrate our results with epigenomic profiling data to define how epigenetic marks, nucleosome occupancy, and cis regulatory element proximity influence the effects of histone acetylation at human enhancers and promoters. We will also use mass spectrometry, dCas9-based transcriptional activators and HATs, and genome-scale knockout screening to define the proteins/protein complexes that support histone acetylation-based gene activation (Aim 2). Finally, we will establish the impact of precisely targeted histone acetylation/deacetylation on enhancer activity and enhancer-promoter interactions (Aim 3). Experiments will be conducted at testbed human loci that have broad significance to human health and mechanistic epigenetics, and that will serve as proof-of-principle for interrogating virtually any regulatory element or locus in the human genome in future efforts. To accomplish the aims of this project, we have assembled an experienced team with synergistic expertise in CRISPR/Cas- based epigenome editing, histone PTM analysis, and functional dissection of enhancer activity.
项目总结/文摘

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Isaac Hilton其他文献

Isaac Hilton的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Isaac Hilton', 18)}}的其他基金

Engineering Therapeutic Human Immune Cells with Modular Self-contained Genetic Circuits
具有模块化独立遗传电路的工程治疗性人类免疫细胞
  • 批准号:
    10617360
  • 财政年份:
    2021
  • 资助金额:
    $ 56.88万
  • 项目类别:
Engineering Therapeutic Human Immune Cells with Modular Self-contained Genetic Circuits
具有模块化独立遗传电路的工程治疗性人类免疫细胞
  • 批准号:
    10303600
  • 财政年份:
    2021
  • 资助金额:
    $ 56.88万
  • 项目类别:
Site-specific control of human gene regulation for therapeutically applicable mechanistic insights
人类基因调控的位点特异性控制以获得治疗上适用的机制见解
  • 批准号:
    10282969
  • 财政年份:
    2021
  • 资助金额:
    $ 56.88万
  • 项目类别:
Site-specific control of human gene regulation for therapeutically applicable mechanistic insights
人类基因调控的位点特异性控制以获得治疗上适用的机制见解
  • 批准号:
    10488643
  • 财政年份:
    2021
  • 资助金额:
    $ 56.88万
  • 项目类别:
Site-specific control of human gene regulation for therapeutically applicable mechanistic insights (R35GM143532)
人类基因调控的位点特异性控制以获得治疗上适用的机制见解(R35GM143532)
  • 批准号:
    10807287
  • 财政年份:
    2021
  • 资助金额:
    $ 56.88万
  • 项目类别:
Site-specific control of human gene regulation for therapeutically applicable mechanistic insights
人类基因调控的位点特异性控制以获得治疗上适用的机制见解
  • 批准号:
    10640172
  • 财政年份:
    2021
  • 资助金额:
    $ 56.88万
  • 项目类别:
Engineering Therapeutic Human Immune Cells with Modular Self-contained Genetic Circuits
具有模块化独立遗传电路的工程治疗性人类免疫细胞
  • 批准号:
    10430257
  • 财政年份:
    2021
  • 资助金额:
    $ 56.88万
  • 项目类别:

相似海外基金

CAREER: Efficient Algorithms for Modern Computer Architecture
职业:现代计算机架构的高效算法
  • 批准号:
    2339310
  • 财政年份:
    2024
  • 资助金额:
    $ 56.88万
  • 项目类别:
    Continuing Grant
Hardware-aware Network Architecture Search under ML Training workloads
ML 训练工作负载下的硬件感知网络架构搜索
  • 批准号:
    2904511
  • 财政年份:
    2024
  • 资助金额:
    $ 56.88万
  • 项目类别:
    Studentship
CAREER: Creating Tough, Sustainable Materials Using Fracture Size-Effects and Architecture
职业:利用断裂尺寸效应和架构创造坚韧、可持续的材料
  • 批准号:
    2339197
  • 财政年份:
    2024
  • 资助金额:
    $ 56.88万
  • 项目类别:
    Standard Grant
Travel: Student Travel Support for the 51st International Symposium on Computer Architecture (ISCA)
旅行:第 51 届计算机体系结构国际研讨会 (ISCA) 的学生旅行支持
  • 批准号:
    2409279
  • 财政年份:
    2024
  • 资助金额:
    $ 56.88万
  • 项目类别:
    Standard Grant
Understanding Architecture Hierarchy of Polymer Networks to Control Mechanical Responses
了解聚合物网络的架构层次结构以控制机械响应
  • 批准号:
    2419386
  • 财政年份:
    2024
  • 资助金额:
    $ 56.88万
  • 项目类别:
    Standard Grant
I-Corps: Highly Scalable Differential Power Processing Architecture
I-Corps:高度可扩展的差分电源处理架构
  • 批准号:
    2348571
  • 财政年份:
    2024
  • 资助金额:
    $ 56.88万
  • 项目类别:
    Standard Grant
Collaborative Research: Merging Human Creativity with Computational Intelligence for the Design of Next Generation Responsive Architecture
协作研究:将人类创造力与计算智能相结合,设计下一代响应式架构
  • 批准号:
    2329759
  • 财政年份:
    2024
  • 资助金额:
    $ 56.88万
  • 项目类别:
    Standard Grant
The architecture and evolution of host control in a microbial symbiosis
微生物共生中宿主控制的结构和进化
  • 批准号:
    BB/X014657/1
  • 财政年份:
    2024
  • 资助金额:
    $ 56.88万
  • 项目类别:
    Research Grant
RACCTURK: Rock-cut Architecture and Christian Communities in Turkey, from Antiquity to 1923
RACCTURK:土耳其的岩石建筑和基督教社区,从古代到 1923 年
  • 批准号:
    EP/Y028120/1
  • 财政年份:
    2024
  • 资助金额:
    $ 56.88万
  • 项目类别:
    Fellowship
NSF Convergence Accelerator Track M: Bio-Inspired Surface Design for High Performance Mechanical Tracking Solar Collection Skins in Architecture
NSF Convergence Accelerator Track M:建筑中高性能机械跟踪太阳能收集表皮的仿生表面设计
  • 批准号:
    2344424
  • 财政年份:
    2024
  • 资助金额:
    $ 56.88万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了