YTHDF3 as a critical regulator of cardiac function

YTHDF3 作为心脏功能的关键调节因子

基本信息

  • 批准号:
    10676427
  • 负责人:
  • 金额:
    $ 4.29万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-07-01 至 2026-06-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY As the global leading cause of death, heart failure is a major challenge for researchers in their quest to discover therapeutics that can save countless lives. After cardiac injury, the heart begins to remodel itself in a way that is initially adaptive, but this innate coping mechanism may over time expedite heart failure onset. Elucidating the mechanisms which underly the progression from adaptive cardiac hypertrophic remodeling to heart failure will dramatically impact the discovery of novel therapeutics for this deadly disease. While regulation of gene expression through transcription of messenger RNA (mRNA) has been extensively studied, only recently an appreciation for the importance of chemical modifications that can occur on mRNA has emerged. This proposal focuses on the methylation of the N6-Adenosine of mRNA (m6A), which is the most abundant internal mRNA modification in eukaryotes. Previous research from our lab has shown that modulation of m6A content in the heart is sufficient to drive cardiac remodeling and to affect the ability of the heart to respond to stress. Despite this, the exact mechanisms through which this occurs is not well understood. The fate of m6A-modified mRNAs is regulated by members of the YTH Domain Family (YTHDF). We found that YTHDF3 is specifically important in cardiomyocytes, where it localizes to the nucleus and binds to Myocyte Enhancer Factor 2D (MEF2D), which is an important transcription factor regulating hypertrophic cardiac growth. Further, we have found that knockout of YTHDF3 mitigates pathological remodeling following pressure overload injury. Given these preliminary data, we hypothesize that YTHDF3 regulates cardiomyocyte size and stress-induced remodeling by modulating the processing of m6A-modified mRNAs transcribed by MEF2D. To test this hypothesis, we already generated and validated a new mouse line in which YTHDF3 can be selectively deleted in cardiomyocytes (YTHDF3-cKO). In Aim 1, we will investigate the role of YTHDF3 at baseline and in the stressed murine heart using longitudinal echocardiography analysis, and assessing histological and molecular signs of pathology at the terminal time point. In Aim 2, we will determine the mechanism through which YTHDF3 regulates the fate of specific subsets of MEF2D-transcribed m6A-mRNAs in cardiomyocytes. First, we will further characterize the binding between YTHDF3 and MEF2D by defining the respective domains involved. Then, we will dissect the binding of YTHDF3 to MEF2D mRNA targets and determine consequent stability, export, and translation of these transcripts. Finally, in Aim 3, we will undertake an unbiased approach to more globally investigate the role of YTHDF3 in regulating mRNA biology in healthy and stressed adult cardiomyocytes by cross-linking immunoprecipitations of YTHDF3-bound mRNAs followed by sequencing (CLIP-seq). Our approach is innovative and significant, as it will be the first project to define the role of YTHDF3 in the heart, which may lead to a new field of therapeutics based on the biology of mRNA methylation.
项目摘要 作为全球死亡的主要原因,心力衰竭是研究人员寻求发现的主要挑战 可以挽救无数生命的治疗剂。心脏损伤后,心脏开始以一种方式重塑自己 最初是适应性的,但是这种天生的应对机制可能会随着时间的流逝加快心力衰竭。阐明 从自适应心脏肥厚型重塑到心力衰竭的发展的机制将 对这种致命疾病的新疗法的发现极大地影响。而基因的调节 通过Messenger RNA(mRNA)的转录表达已经进行了广泛的研究,直到最近 人们已经出现了对MRNA上可能发生的化学修饰的重要性的欣赏。这个建议 专注于mRNA的N6-腺苷(M6A)的甲基化,这是最丰富的内部mRNA 真核生物的修改。我们实验室的先前研究表明,M6A含量的调制 心脏足以驱动心脏重塑并影响心脏对压力的反应能力。尽管 这是尚不清楚发生这种情况的确切机制。 M6A修饰的mRNA的命运 由Yth域家族(YTHDF)的成员监管。我们发现YTHDF3特别重要 在心肌细胞中,它位于核与肌细胞增强子因子2D(MEF2D)结合到其中 是调节肥厚性心脏生长的重要转录因子。此外,我们发现淘汰赛 YTHDF3的压力过多损伤后会减轻病理重塑。鉴于这些初步数据, 我们假设YTHDF3调节心肌细胞的大小和应力诱导的重塑。 MEF2D转录的M6A修饰mRNA的处理。为了检验这一假设,我们已经 生成并验证了一条新的鼠标线,在该系列中可以选择性地删除YTHDF3的心肌细胞 (ythdf3-cko)。在AIM 1中,我们将研究YTHDF3在基线和压力鼠心脏中的作用 使用纵向超声心动图分析,并评估病理学的组织学和分子迹象 终端时间点。在AIM 2中,我们将确定YTHDF3调节命运的机制 心肌细胞中MEF2D转录的M6A-MRNA的特定子集。首先,我们将进一步描述 通过定义所涉及的各个域,在YTHDF3和ME​​F2D之间结合。然后,我们将剖析 YTHDF3与MEF2D mRNA靶标结合,并确定这些稳定性,导出和翻译 成绩单。最后,在AIM 3中,我们将采取一种公正的方法,以更全球调查的作用 YTHDF3在调节健康和压力的成人心肌细胞中的mRNA生物学方面通过交联 YTHDF3结合的mRNA的免疫沉淀,然后进行测序(夹子seq)。我们的方法是创新的 重要的是,这将是第一个定义YTHDF3在心脏中的作用的项目,这可能会导致新的 基于mRNA甲基化生物学的治疗领域。

项目成果

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Charles P. Rabolli其他文献

Nanopore Detection of METTL3-Dependent m6A-Modified mRNA Reveals a New Mechanism Regulating Cardiomyocyte Mitochondrial Metabolism.
METTL3 依赖性 m6A 修饰 mRNA 的纳米孔检测揭示了调节心肌细胞线粒体代谢的新机制。
  • DOI:
    10.1161/circulationaha.123.066473
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    37.8
  • 作者:
    Charles P. Rabolli;Isabel S. Naarmann;C. Makarewich;Kedryn K. Baskin;Christoph Dieterich;Federica Accornero
  • 通讯作者:
    Federica Accornero
Cardiac cryptographers: cracking the code of the epitranscriptome
心脏密码学家:破解表观转录组的密码
  • DOI:
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    39.3
  • 作者:
    Charles P. Rabolli;Federica Accornero
  • 通讯作者:
    Federica Accornero

Charles P. Rabolli的其他文献

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