High-throughput functional characterization of human enhancers

人类增强子的高通量功能表征

基本信息

  • 批准号:
    10241101
  • 负责人:
  • 金额:
    $ 75.05万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-08-18 至 2023-01-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT: The genomes of higher organisms and their expression are highly regulated in response to a variety of developmental, environmental, and nutritional cues. The failure to execute proper gene regulation can lead to developmental defects and disease states. The overarching goal of this research is to understand basic regulatory mechanisms of genes at the level of transcription, the stage where RNA polymerase II (Pol II) transcribes the genes into mRNA. This regulation is conducted by the concerted effort of DNA elements (promoters and enhancers) and many protein machineries such as Pol II, TFs, and chromatin/histone modifying complexes. Recent studies in Drosophila and mammalian cells have revealed that transcription is primarily regulated at two rate-limiting steps; 1) Recruitment of Pol II to promoter and Pol II pausing at 20-50bp downstream of transcription initiation site, and 2) Release of paused Pol II to productive elongation. A battery of complementary approaches (some novel) are designed to identify human TFs and chromatin remodelers that act at these steps and then rigorously address the mechanism by which they exert transcriptional regulation. by TFs and chromatin modifiers with the highest possible spatiotemporal resolution genome-wide in distinct cell lines, including K562, HCT116, HEK293, and undifferentiated and differentiated WTC-11. The wealth of existing information in these cell lines will be complemented with Run-On assays (RO-seq), and others when necessary, to identify TFs that act primarily on one or both of the rate-limiting regulated steps in transcription. These observational assays include multiple highly-sensitive RO-seq assays for mapping the position and amount of transcription across genes and enhancers genome-wide, ChIP-exo for detecting TF binding and occupancy, STARR-seq assays to measure transcription regulatory activity of enhancers and promoters, and a degron system to rapidly degrade TFs to assess their primary effects by these ‘-seq’ assays. Together, these systems will test our regulatory models and assess their generality. In Aim 1, using a novel aptamer-based pulldown and mass spectrometry approach, we will identify pioneering TFs that work through remodeling complexes such as PBAP (SWI/SNF) to open chromatin for subsequent TF and Pol II recruitment. In Aim 2, we seek to identify cell- type-specific TFs that act at major regulated steps of transcription, Steps 1, 2, or both. This will be achieved by a comparative analysis of cell line specific nascent transcription profiles. Aim 3 will test the role of TF candidates, which are associated with one or both of the regulatory steps in the transcription cycle, in living cells using a Degron approach and multiple ‘-seq’ assays. In Aim 4, we will assess the roles of TFs in the interplay of enhancers and promoters interactions using high-throughput episomal and chromosomal enhancer assays. The proposal will identify TFs that act at specific steps in transcription regulation and provide insights to the mechanics of their action.
项目总结/文摘:

项目成果

期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Enhancer transcription: what, where, when, and why?
  • DOI:
    10.1101/gad.311605.118
  • 发表时间:
    2018-01-01
  • 期刊:
  • 影响因子:
    10.5
  • 作者:
    Tippens ND;Vihervaara A;Lis JT
  • 通讯作者:
    Lis JT
RNA polymerase mapping in plants identifies intergenic regulatory elements enriched in causal variants.
  • DOI:
    10.1093/g3journal/jkab273
  • 发表时间:
    2021-10-19
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Lozano R;Booth GT;Omar BY;Li B;Buckler ES;Lis JT;Del Carpio DP;Jannink JL
  • 通讯作者:
    Jannink JL
Stress-induced transcriptional memory accelerates promoter-proximal pause release and decelerates termination over mitotic divisions.
  • DOI:
    10.1016/j.molcel.2021.03.007
  • 发表时间:
    2021-04-15
  • 期刊:
  • 影响因子:
    16
  • 作者:
    Vihervaara A;Mahat DB;Himanen SV;Blom MAH;Lis JT;Sistonen L
  • 通讯作者:
    Sistonen L
Pioneer-like factor GAF cooperates with PBAP (SWI/SNF) and NURF (ISWI) to regulate transcription.
  • DOI:
    10.1101/gad.341768.120
  • 发表时间:
    2021-01-01
  • 期刊:
  • 影响因子:
    10.5
  • 作者:
    Judd J;Duarte FM;Lis JT
  • 通讯作者:
    Lis JT
Chromatin-mediated epigenetic regulation of HSV-1 transcription as a potential target in antiviral therapy.
  • DOI:
    10.1016/j.antiviral.2021.105103
  • 发表时间:
    2021-08
  • 期刊:
  • 影响因子:
    7.6
  • 作者:
    Schang LM;Hu M;Cortes EF;Sun K
  • 通讯作者:
    Sun K
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JOHN T LIS其他文献

JOHN T LIS的其他文献

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{{ truncateString('JOHN T LIS', 18)}}的其他基金

Functional Architecture and Interplay of Transcription Regulatory Elements of the Human Genome
人类基因组转录调控元件的功能结构和相互作用
  • 批准号:
    10639574
  • 财政年份:
    2023
  • 资助金额:
    $ 75.05万
  • 项目类别:
High-throughput functional characterization of human enhancers
人类增强子的高通量功能表征
  • 批准号:
    10166068
  • 财政年份:
    2020
  • 资助金额:
    $ 75.05万
  • 项目类别:
Tissue biology studies of histone modification, nascent transcription, and post-transcription regulation
组蛋白修饰、新生转录和转录后调控的组织生物学研究
  • 批准号:
    10746577
  • 财政年份:
    2018
  • 资助金额:
    $ 75.05万
  • 项目类别:
High-throughput functional characterization of human enhancers
人类增强子的高通量功能表征
  • 批准号:
    9904754
  • 财政年份:
    2017
  • 资助金额:
    $ 75.05万
  • 项目类别:
Distance-Hi-C: Creating Photo Activated X-linkers To Define Nuclear Architecture
Distance-Hi-C:创建光激活 X 链接器来定义核架构
  • 批准号:
    9769846
  • 财政年份:
    2015
  • 资助金额:
    $ 75.05万
  • 项目类别:
Distance-Hi-C: Creating Photo Activated X-linkers To Define Nuclear Architecture
Distance-Hi-C:创建光激活 X 链接器来定义核架构
  • 批准号:
    9000948
  • 财政年份:
    2015
  • 资助金额:
    $ 75.05万
  • 项目类别:
Distance-Hi-C: Creating Photo Activated X-linkers To Define Nuclear Architecture
Distance-Hi-C:创建光激活 X 链接器来定义核架构
  • 批准号:
    9144434
  • 财政年份:
    2015
  • 资助金额:
    $ 75.05万
  • 项目类别:
Factor-general characterization of dynamic transcriptional stress responses
动态转录应激反应的因子一般特征
  • 批准号:
    8846643
  • 财政年份:
    2013
  • 资助金额:
    $ 75.05万
  • 项目类别:
Factor-general characterization of dynamic transcriptional stress responses
动态转录应激反应的因子一般特征
  • 批准号:
    8578768
  • 财政年份:
    2013
  • 资助金额:
    $ 75.05万
  • 项目类别:
Factor-general characterization of dynamic transcriptional stress responses
动态转录应激反应的因子一般特征
  • 批准号:
    8729397
  • 财政年份:
    2013
  • 资助金额:
    $ 75.05万
  • 项目类别:

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