Role of BRD4 in Normal Hematopoiesis and Hematopoietic Stem Cell Biology

BRD4 在正常造血和造血干细胞生物学中的作用

基本信息

  • 批准号:
    10741506
  • 负责人:
  • 金额:
    $ 7.91万
  • 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:
    2021-12-01 至 2024-11-30
  • 项目状态:
    已结题

项目摘要

Bromodomain-containing protein 4 (BRD4) is a member of the BET (bromodomain and extra terminal domain) family proteins that also include BRD2, BRD3, and BRDT. BRD4 facilitates the initiation and elongation of transcription by binding to acetylated lysine residues of histone tails to promote the recruitment of the RNA polymerase II complex to sites of active transcription. Since BRD4 is required for MYC oncogene expression, BRD4 inhibition represents an attractive strategy to target MYC-dependent cancers via small-molecule inhibitors. BRD4 is over-expression in both solid tumors and myeloid malignancies, including acute myeloid leukemia (AML). BET inhibitors (BETi) have been shown to have efficacy against various types of tumors, especially MYC-driven cancers. Despite robust studies of BRD4 in solid tumors, the role of BRD4 in normal hematopoiesis and the impact of BRD4 overexpression on the pathogenesis of hematological malignancies remain largely unknown. Filling this critical gap of knowledge is the primary goal of this 3-year SHINE application. In the current project, we aim to determine the roles of BRD4 in hematopoietic stem/progenitor cells (HSC/HPCs) function and explore whether Brd4 overexpression affects HSC/HPC cell fate and leukemic transformation. Using a conditional Brd4 knock- out (Mx1Cre;Brd4f/f) mouse model, we found that while heterozygous deletion of Brd4 in mice did not cause noticeable changes in hematopoiesis, homozygous deletion of Brd4 in the hematopoietic system quickly diminished HSC/HPCs and pan lineage cells due to the induction of apoptosis. Therefore, the conditional Brd4 knock-out mouse model alone is not suitable for studying the hidden role of BRD4 in HSC/HPC functions. We thus generated several Brd4 transgenic (Tg) mouse lines with different levels of BRD4 transgene expression (ranging from 25% to 200%). Our preliminary data showed that overexpression of BRD4 (Brd4200%Tg) in hematopoietic cells altered HSC/HPC pools in vivo and increased HSC/HPC replating potential in vitro. Interestingly, re-expression of a lower level of BRD4 in Brd4Δ/Δ BMMNCs (Brd4Δ/Δ;Brd425%Tg) significantly increased the cell survival and the frequencies of CFU-Cs. We hypothesize that a hypomorph BRD4 mouse model (Mx1Cre;Brd4f/f;Brd425%Tg), by expressing a protectable level of BRD4 in hematopoiesis which allow for HSC/HPC survival, would suit better for evaluating the hidden role of BRD4 in HSC/HPC functions. We will also examine whether BETi affect normal hematopoiesis in mice. Furthermore, we will decipher how BRD4 regulates the HSC/HPCs functions by assessing genome-wide BRD4, P-TEFb, Pol-II, H3K27ac, and H3K122ac occupancies in HSC/HPCs and correlating with the gene expression outputs. These studies are timely and fundamentally crucial for filling an essential and critical gap of knowledge towards uncovering the hidden roles of BRD4 in normal and malignant hematopoiesis, thus fill a critical gap in knowledge on Brd4 in hematopoiesis and BETi for the treatment of hematopoietic malignancies.
含溴结构域蛋白4(Bromodomain-containing protein 4,BRD4)是BET(bromodomain and extra terminal domain,溴结构域和额外末端结构域)的成员。 家族蛋白质,还包括BRD2、BRD3和BRDT。BRD4促进了细胞的启动和延长, 通过与组蛋白尾部的乙酰化赖氨酸残基结合以促进RNA的募集来转录 聚合酶II复合物的活性转录位点。由于BRD4是MYC癌基因表达所必需的, BRD4抑制代表了通过小分子抑制剂靶向MYC依赖性癌症的有吸引力的策略。 BRD4在实体瘤和骨髓恶性肿瘤(包括急性髓性白血病(AML))中均过表达。 BET抑制剂(BETi)已被证明对各种类型的肿瘤具有功效,尤其是MYC驱动的肿瘤。 癌的尽管对BRD4在实体瘤中的作用进行了强有力的研究,但BRD4在正常造血中的作用和BRD4在肿瘤中的作用仍然是未知的。 BRD4过表达对血液恶性肿瘤发病机制的影响在很大程度上仍是未知的。 填补这一关键的知识空白是这个为期3年的SHINE应用程序的主要目标。在目前的项目中, 我们的目的是确定BRD4在造血干/祖细胞(HSC/HPC)功能中的作用, 探索Brd4过表达是否影响HSC/HPC细胞命运和白血病转化。使用 在条件性Brd4基因敲除(Mx1Cre; Brd4f/f)小鼠模型中,我们发现Brd4基因杂合缺失 在小鼠的造血中没有引起明显的变化,造血中Brd4的纯合缺失, 系统由于诱导凋亡而迅速减少HSC/HPCs和泛系细胞。因此 单独的条件性Brd4敲除小鼠模型不适合于研究BRD4在 HSC/HPC功能。因此,我们产生了几种具有不同BRD4水平的Brd4转基因(Tg)小鼠系 转基因表达(范围从25%至200%)。我们的初步数据显示BRD4的过表达 在造血细胞中,Brd 4200%Tg改变了体内HSC/HPC池,并增加了HSC/HPC再铺板潜力 体外有趣的是,在Brd4 Δ/Δ BMMNC(Brd4 Δ/Δ; Brd425%Tg)中重新表达较低水平的BRD4, 显着增加细胞存活率和CFU-Cs频率。我们假设一个亚型体 BRD4小鼠模型(Mx1Cre; Brd4f/f; Brd425%Tg),通过在造血中表达可保护水平的BRD4, 这使得HSC/HPC存活,将更适合于评估BRD4在HSC/HPC中的隐藏作用 功能协调发展的我们还将检查BETi是否影响小鼠中的正常造血。此外,我们将 通过评估全基因组BRD4,P-TEFb,Pol-II, H3K27ac和H3K122ac在HSC/HPC中存在,并与基因表达产物相关。这些 研究是及时的,对于填补知识的基本和关键差距至关重要, 揭示BRD4在正常和恶性造血中的隐藏作用,从而填补了 关于造血中的Brd4和用于治疗造血系统恶性肿瘤的BETi的知识。

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 }}

Feng-Chun Yang其他文献

Feng-Chun Yang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('Feng-Chun Yang', 18)}}的其他基金

Role of BRD4 in Normal Hematopoiesis and Hematopoietic Stem Cell Biology_
BRD4在正常造血和造血干细胞生物学中的作用_
  • 批准号:
    10610534
  • 财政年份:
    2022
  • 资助金额:
    $ 7.91万
  • 项目类别:
Role of BRD4 in Normal Hematopoiesis and Hematopoietic Stem Cell Biology.
BRD4 在正常造血和造血干细胞生物学中的作用。
  • 批准号:
    10610129
  • 财政年份:
    2022
  • 资助金额:
    $ 7.91万
  • 项目类别:
Role of BRD4 in Normal Hematopoiesis and Hematopoietic Stem Cell Biology
BRD4 在正常造血和造血干细胞生物学中的作用
  • 批准号:
    10741507
  • 财政年份:
    2021
  • 资助金额:
    $ 7.91万
  • 项目类别:
Role of BRD4 in Normal Hematopoiesis and Hematopoietic Stem Cell Biology
BRD4 在正常造血和造血干细胞生物学中的作用
  • 批准号:
    10531914
  • 财政年份:
    2021
  • 资助金额:
    $ 7.91万
  • 项目类别:
Role of BRD4 in Normal Hematopoiesis and Hematopoietic Stem Cell Biology
BRD4 在正常造血和造血干细胞生物学中的作用
  • 批准号:
    10384169
  • 财政年份:
    2021
  • 资助金额:
    $ 7.91万
  • 项目类别:
Role of PHF6 in Normal Hematopoiesis and hematopoietic stem cell biology
PHF6 在正常造血和造血干细胞生物学中的作用
  • 批准号:
    9977271
  • 财政年份:
    2019
  • 资助金额:
    $ 7.91万
  • 项目类别:
Role of PHF6 in Normal Hematopoiesis and hematopoietic stem cell biology
PHF6 在正常造血和造血干细胞生物学中的作用
  • 批准号:
    10063768
  • 财政年份:
    2019
  • 资助金额:
    $ 7.91万
  • 项目类别:
Role of PHF6 in Normal Hematopoiesis and hematopoietic stem cell biology
PHF6 在正常造血和造血干细胞生物学中的作用
  • 批准号:
    10198036
  • 财政年份:
    2019
  • 资助金额:
    $ 7.91万
  • 项目类别:

相似海外基金

NSF-BSF: Towards a Molecular Understanding of Dynamic Active Sites in Advanced Alkaline Water Oxidation Catalysts
NSF-BSF:高级碱性水氧化催化剂动态活性位点的分子理解
  • 批准号:
    2400195
  • 财政年份:
    2024
  • 资助金额:
    $ 7.91万
  • 项目类别:
    Standard Grant
Collaborative Research: Beyond the Single-Atom Paradigm: A Priori Design of Dual-Atom Alloy Active Sites for Efficient and Selective Chemical Conversions
合作研究:超越单原子范式:双原子合金活性位点的先验设计,用于高效和选择性化学转化
  • 批准号:
    2334970
  • 财政年份:
    2024
  • 资助金额:
    $ 7.91万
  • 项目类别:
    Standard Grant
Collaborative Research: Beyond the Single-Atom Paradigm: A Priori Design of Dual-Atom Alloy Active Sites for Efficient and Selective Chemical Conversions
合作研究:超越单原子范式:双原子合金活性位点的先验设计,用于高效和选择性化学转化
  • 批准号:
    2334969
  • 财政年份:
    2024
  • 资助金额:
    $ 7.91万
  • 项目类别:
    Standard Grant
Mechanochemical synthesis of nanocarbon and design of active sites for oxygen reducton/evolution reactions
纳米碳的机械化学合成和氧还原/演化反应活性位点的设计
  • 批准号:
    23K04919
  • 财政年份:
    2023
  • 资助金额:
    $ 7.91万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Creation of porous inorganic frameworks with controlled structure of metal active sites by the building block method.
通过积木法创建具有金属活性位点受控结构的多孔无机框架。
  • 批准号:
    22KJ2957
  • 财政年份:
    2023
  • 资助金额:
    $ 7.91万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Catalysis of Juxaposed Active Sites Created in Nanospaces and Their Applications
纳米空间中并置活性位点的催化及其应用
  • 批准号:
    23K04494
  • 财政年份:
    2023
  • 资助金额:
    $ 7.91万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Generation of carbon active sites by modifying the oxygen containing functional groups and structures of carbons for utilizing to various catalytic reactions.
通过修饰碳的含氧官能团和结构来产生碳活性位点,用于各种催化反应。
  • 批准号:
    23K13831
  • 财政年份:
    2023
  • 资助金额:
    $ 7.91万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
CAREER: CAS: Understanding the Chemistry of Palladium and Silyl Compounds to Design Catalyst Active Sites
职业:CAS:了解钯和甲硅烷基化合物的化学性质以设计催化剂活性位点
  • 批准号:
    2238379
  • 财政年份:
    2023
  • 资助金额:
    $ 7.91万
  • 项目类别:
    Continuing Grant
CAS: Collaborative Research: Tailoring the Distribution of Transient vs. Dynamic Active Sites in Solid-Acid Catalysts and Their Impacts on Chemical Conversions
CAS:合作研究:定制固体酸催化剂中瞬时活性位点与动态活性位点的分布及其对化学转化的影响
  • 批准号:
    2154399
  • 财政年份:
    2022
  • 资助金额:
    $ 7.91万
  • 项目类别:
    Standard Grant
Engineering of Active Sites in Heterogeneous Catalysts for Sustainable Chemical and Fuel Production.
用于可持续化学和燃料生产的多相催化剂活性位点工程。
  • 批准号:
    RGPIN-2019-06633
  • 财政年份:
    2022
  • 资助金额:
    $ 7.91万
  • 项目类别:
    Discovery Grants Program - Individual
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了