Regulation and Function of Alternative mRNA Isoform Expression in Mammals

哺乳动物中替代 mRNA 同工型表达的调节和功能

基本信息

项目摘要

Summary Most human genes contain introns, and presence of introns often increases the expression of the host gene, a phenomenon known as intron-mediated enhancement (IME). IME has been observed in diverse genes in animals, plants and fungi and often varies in magnitude across introns. However, little is known about how introns impact expression or what intron features modulate IME activity. Recently, we have described a novel phenomenon that we call exon-mediated activation of transcription starts (EMATS), in which the splicing of internal exons impacts the spectrum of promoters used and expression level of the gene. EMATS acts at a distance of up to a few kb, can alter gene expression by at least severalfold, and appears more active at certain promoters – especially intrinsically weak promoters. The detailed sequence requirements and mode of action of EMATS are not yet known. This proposal is seeks to understand the rules that govern IME and EMATS, to improve the prediction of gene expression and to enable methods to modulate gene expression by altering splicing. It is organized around the following aims. SA1. Determine the sequence dependence of intron-mediated enhancement. SA2. Explore the scope and rules for EMATS regulation. In Aim 1, we will generate a library of many thousands of distinct random sequences inserted into an intron in a dual fluorescent reporter system that is chromosomally integrated into human cells. This design will enable high-throughput measurement of the effects of each intron on nascent RNA, mature RNA and protein levels, and these data will be used to identify motifs that enhance or silence expression in a splicing-dependent manner from an intronic location. In aim 2, we will systematically derive and test rules for how EMATS regulation depends on the location and sequence of the internal exon and on properties of the involved promoter. Finally, we will use the information learned about IME and EMATS to improve predictions of gene expression from primary sequence. Together, the research described in these aims will establish rules governing how splicing impacts gene expression in mammalian genomes. Identification of motifs that function as splicing-dependent activators or silencers of expression can be used to improve prediction of expression from genome sequence and may enable detection of intronic variants that alter expression. Understanding how splicing impacts expression may also enable new approaches for gene expression modulation.
总结

项目成果

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CHRISTOPHER B BURGE其他文献

CHRISTOPHER B BURGE的其他文献

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{{ truncateString('CHRISTOPHER B BURGE', 18)}}的其他基金

Regulation and Function of Alternative mRNA Isoform Expression in Mammals
哺乳动物中替代 mRNA 同工型表达的调节和功能
  • 批准号:
    10323056
  • 财政年份:
    2021
  • 资助金额:
    $ 52.87万
  • 项目类别:
RNA-Binding Proteins as Molecular Integrators that Control the Response of HGSOC to Ant-Cancer Therapies
RNA 结合蛋白作为分子整合剂控制 HGSOC 对抗癌疗法的反应
  • 批准号:
    10524771
  • 财政年份:
    2018
  • 资助金额:
    $ 52.87万
  • 项目类别:
RNA-Binding Proteins as Molecular Integrators that Control the Response of HGSOC to Ant-Cancer Therapies
RNA 结合蛋白作为分子整合剂控制 HGSOC 对抗癌疗法的反应
  • 批准号:
    10054974
  • 财政年份:
    2018
  • 资助金额:
    $ 52.87万
  • 项目类别:
RNA-Binding Proteins as Molecular Integrators that Control the Response of HGSOC to Ant-Cancer Therapies
RNA 结合蛋白作为分子整合剂控制 HGSOC 对抗癌疗法的反应
  • 批准号:
    10305607
  • 财政年份:
    2018
  • 资助金额:
    $ 52.87万
  • 项目类别:
Bioinformatics
生物信息学
  • 批准号:
    9149750
  • 财政年份:
    2015
  • 资助金额:
    $ 52.87万
  • 项目类别:
Dynamics of Gene and Isoform Regulation during EMT and tumor progression
EMT 和肿瘤进展过程中基因和亚型调控的动态
  • 批准号:
    8684871
  • 财政年份:
    2014
  • 资助金额:
    $ 52.87万
  • 项目类别:
Dynamics of Gene and Isoform Regulation during EMT and tumor progression
EMT 和肿瘤进展过程中基因和亚型调控的动态
  • 批准号:
    8852097
  • 财政年份:
    2014
  • 资助金额:
    $ 52.87万
  • 项目类别:
Development of technologies for genome-wide identification of RNA branch points
RNA分支点全基因组鉴定技术的开发
  • 批准号:
    8310598
  • 财政年份:
    2012
  • 资助金额:
    $ 52.87万
  • 项目类别:
Development of technologies for genome-wide identification of RNA branch points
RNA分支点全基因组鉴定技术的开发
  • 批准号:
    8628858
  • 财政年份:
    2012
  • 资助金额:
    $ 52.87万
  • 项目类别:
Development of technologies for genome-wide identification of RNA branch points
RNA分支点全基因组鉴定技术的开发
  • 批准号:
    8463015
  • 财政年份:
    2012
  • 资助金额:
    $ 52.87万
  • 项目类别:

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