Investigating how transcription factors cooperate and overcome the enhancer nucleosome barrier during embryonic patterning

研究胚胎模式形成过程中转录因子如何合作并克服增强子核小体屏障

基本信息

项目摘要

Project Summary This misregulation of gene expression underlies several human diseases, including many cancers, diabetes, obesity, and multiple developmental disorders. Genome-wide studies and next-generation sequencing have revealed that sequence variants in enhancers, cis-regulatory DNA sequences that control spaciotemporal gene expression programs, contribute to the development of these diseases. These mutations often affect enhancer activity, which must be tightly controlled since enhancers drive tissue and cell-type specific gene expression patterns. One way that enhancer activity is controlled is through the regulation of enhancer accessibility by the nucleosome: the structural unit of chromatin comprised of 147 bp of DNA and a histone octamer. Enhancers are characterized by an intrinsically strong nucleosome barrier that prevents the binding of transcription factors (TFs), the proteins that activate enhancers, until the proper context for activation is reached, at which point TFs must overcome the nucleosome barrier and bind to the DNA. While nucleosome depletion is a key early step in enhancer activation, we do not yet understand how the nucleosome barrier is overcome and how enhancers are made accessible for gene activation, despite accessibility being a major regulator of enhancer activity. Current models suggest that specialized TFs called pioneer factors can access their motifs in the presence of nucleosomes and foment nucleosome depletion through cooperativity with additional TFs. Even still, how pioneer and non-pioneer TFs cooperate to generate chromatin accessibility at enhancers is not yet known. Furthermore, how pioneer factors perturb the nucleosomal landscape to facilitate chromatin accessibility and cooperative TF binding is unclear. This study seeks to identify how TFs overcome the nucleosome barrier at enhancers using high-resolution experimental and computational genomics techniques to map TF binding, chromatin accessibility, and nucleosome positioning. Aim 1 will characterize how pioneer and non-pioneer TFs cooperate for binding to the DNA and for establishing chromatin accessibility. This aim will combine high-resolution TF binding (ChIP- nexus) and temporally resolved chromatin accessibility (time-course ATAC-seq) information with deep learning models (BPNet) that will reveal the sequences and sequence constraints that are important for and predictive of TF cooperativity. Aim 2 will profile genome-wide nucleosome positional changes over developmental time at unprecedented resolution, using a chemical mapping of nucleosome centers approach. This aim will uncover how the nucleosome state at enhancers is altered over time to generate accessibility and how nucleosomes are positioned with respect to the underlying regulatory DNA sequences. Taken together, these aims will illuminate how TFs pioneer the chromatin landscape for enhancer activation, thereby deepening the field’s understanding of the mechanisms of gene regulation and how misregulation contributes to human disease.
项目摘要 这种基因表达的失调是几种人类疾病的基础,包括许多癌症、糖尿病、 肥胖和多种发育障碍。全基因组研究和下一代测序已经 揭示了控制时空基因的增强子、顺式调节DNA序列中的序列变体 表达程序,有助于这些疾病的发展。这些突变通常会影响增强子 活性,必须严格控制,因为增强子驱动组织和细胞类型特异性基因表达 模式.控制增强子活性的一种方式是通过调节增强子的可及性, 核小体:染色质的结构单位,由147 bp的DNA和组蛋白八聚体组成。增强剂 其特征在于固有的强核小体屏障,其阻止转录因子的结合 (TFs)激活增强子的蛋白质,直到达到激活的适当环境,此时TF 必须克服核小体屏障与DNA结合。虽然核小体消耗是一个关键的早期步骤, 增强子激活,我们还不知道如何克服核小体障碍,以及增强子如何激活核小体。 尽管可接近性是增强子活性的主要调节因子,但可接近性对于基因激活是可接近的。 目前的模型表明,被称为先锋因子的特化TF可以在以下情况下访问它们的基序: 核小体并通过与另外的TF的协同性引起核小体消耗。即便如此, 先驱和非先驱TF合作在增强子处产生染色质可及性尚不清楚。 此外,先锋因子如何扰乱核小体景观,以促进染色质的可及性, 协同TF结合尚不清楚。 本研究旨在利用高分辨率的荧光显微镜, 实验和计算基因组学技术,以映射TF结合,染色质可及性, 核小体定位目标1将说明先驱和非先驱工作队如何合作, DNA并用于建立染色质可及性。这一目标将结合联合收割机高分辨率TF结合(ChIP- nexus)和时间分辨的染色质可及性(时程ATAC-seq)信息 模型(BPNet),将揭示序列和序列约束,这是重要的和预测 TF协同性Aim 2将描绘全基因组核小体在发育过程中的位置变化, 前所未有的分辨率,使用核小体中心的化学作图方法。这一目标将揭示 增强子处的核小体状态如何随时间改变以产生可及性,以及核小体如何 相对于底层调控DNA序列定位。综合起来,这些目标将 阐明了TF如何开拓染色质景观增强子激活,从而加深了该领域的 了解基因调控机制以及调控不当如何导致人类疾病。

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 }}

Kaelan Joseph Brennan其他文献

Kaelan Joseph Brennan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('Kaelan Joseph Brennan', 18)}}的其他基金

Investigating how transcription factors cooperate and overcome the enhancer nucleosome barrier during embryonic patterning
研究胚胎模式形成过程中转录因子如何合作并克服增强子核小体屏障
  • 批准号:
    10462068
  • 财政年份:
    2022
  • 资助金额:
    $ 3.17万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 3.17万
  • 项目类别:
    Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 3.17万
  • 项目类别:
    Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 3.17万
  • 项目类别:
    Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 3.17万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 3.17万
  • 项目类别:
    Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 3.17万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 3.17万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 3.17万
  • 项目类别:
    EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 3.17万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 3.17万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了