Epigenetic control of muscle stem cell function by PASK-Wdr5 signaling

PASK-Wdr5 信号传导对肌肉干细胞功能的表观遗传控制

• 批准号: 10019860
• 负责人: CHINTAN K KIKANI
• 金额: $ 31.98万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-25 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10019860
• 关键词: Acetylation; Acute; Adult; Affect; Age; Aging; Binding; Cell Count; Cell physiology; Cells; Collaborations; Complex; Cues; Data; Disease; Epigenetic Process; Equilibrium; FRAP1 gene; Functional disorder; Genetic Transcription; Goals; Histone H3; Histones; Homeostasis; Human; Injury; Insulin; Legal patent; Lysine; Maintenance; Messenger RNA; Metabolism; Modeling; Modification; Molecular; Mus; Muscle; Muscle Cells; Muscle function; Muscle satellite cell; Muscular Atrophy; Muscular Dystrophies; Myoblasts; Myogenin; Myopathy; Natural regeneration; Nutrient; Pathway interactions; Phosphorylation; Phosphotransferases; Physiological; Play; Population; Process; Proliferating; Property; Protein Kinase; Proteins; Publishing; Reagent; Research; Research Proposals; Role; Signal Pathway; Signal Transduction; Structure; Testing; Therapeutic; Transcription Process; Transferase; Trauma; WD Repeat; Wasting Syndrome; base; functional loss; hormonal signals; human disease; in vivo; inhibitor/antagonist; injured; interest; member; mouse model; muscle aging; myogenesis; normal aging; novel; novel therapeutics; off-patent; overexpression; programs; promoter; recruit; regenerative; response; sarcopenia; self-renewal; stem cell differentiation; stem cell fate specification; stem cells; transcription factor

Project Summary Muscle trauma is one of the most common and repetitive types of injury in humans. Owing to the regenerative functions of Muscle Stem Cells (MuSCs), the injured myotome can fully regain its structural and functional integrity within just a few days. In addition to this remarkable regenerative function, MuSCs also play a significant role in the maintenance of muscle homeostasis under the normal condition. On the other hand, the decline in MuSCs function is implicated in muscle wasting diseases and several forms of muscular dystrophy. The functions of MuSCs are influenced by the niche it occupies. For example, the niche emits signals to regulate MuSCs quiescence in the uninjured state, or activation when regeneration is required. Understanding how these signaling pathways control quiescence and activation of MuSCs is essential to devise the next generation of therapeutic approaches for diseases of MuSCs dysfunction. We recently described a novel signaling pathway in MuSCs that stimulates regenerative myogenesis by epigenetically activating the transcription of the Myog promoter. In this pathway, Per-Arnt-Sim domain Kinase (PASK) phosphorylates WD40-domain repeat 5 (Wdr5) at the onset of the myogenesis program. Phosphorylated Wdr5 stimulates the Myog transcription by inducing histone H3 trimethylation at lysine 4 (H3K4me3) and the recruitment of the MyoD transcription factor at the Myog promoter. We present evidence that PASK expression and activity is induced in regenerating myoblasts by signaling cues such as insulin and nutrients in mTOR complex 1 dependent manner. Functionally, loss of Pask in mice retards regenerative myogenesis, and over-expression of PASK depletes the stem cells. Thus, we hypothesize that PASK plays a role balancing self-renewal vs differentiation during regeneration. Building upon these data, in this proposal, we will investigate how PASK expression and activity is regulated in the regenerating myoblast (Specific Aim 1). In activated MuSCs, PASK phosphorylated Wdr5 induces H3K4me3 modification, MyoD recruitment and nucleosomal remodeling on the Myog promoter yet the mechanism is not clear. In Specific Aim 2, we will extensively study two interacting partners of Wdr5 which could remodel the Myog promoter for its activation. Upon induction of Myogenin, Pax7 expression is down-regulated and terminal differentiation is established. Since PASK is an upstream regulator of the Myog expression, we are interested determining how loss or gain of PASK affects the self-renewing population during regeneration and normal aging process, which we will study in Specific Aim 3. Ultimately, these aims will allow us to understand how niche signaling cues control the balance between self-renewal and differentiation and how it can be exploited for improvement of physiological conditions such as sarcopenia.

项目摘要 肌肉创伤是人类最常见和最重复的损伤类型之一。由于 肌肉干细胞（MuSC）的再生功能，受损的肌节可以完全恢复其结构和功能， 几天之内就恢复了功能除了这种显著的再生功能，MuSCs还发挥着 在正常情况下维持肌肉内稳态的重要作用。另一方面 MuSC功能的下降与肌肉萎缩性疾病和几种形式的肌肉萎缩有关。 营养不良MuSC的功能受其所占据的生态位的影响。例如， 信号调节MuSC在未损伤状态下的静止，或在需要再生时的激活。 了解这些信号通路如何控制MuSC的静止和激活对于设计 下一代MuSCs功能障碍疾病的治疗方法。我们最近描述了一个 MuSC中的新信号传导途径，通过表观遗传激活 Myog启动子的转录。在该途径中，Per-Arnt-Sim结构域激酶（PASK）磷酸化 WD 40-结构域重复序列5（Wdr 5）在肌生成程序开始时。磷酸化Wdr 5刺激 通过诱导组蛋白H3在赖氨酸4处的三甲基化（H3 K4 me 3）来进行Myog转录， MyoD转录因子在Myog启动子处。我们提出的证据表明，PASK的表达和活性 在再生成肌细胞中通过信号线索如mTOR复合物1中的胰岛素和营养素诱导 依赖的方式。在功能上，小鼠中Pask的缺失阻碍了再生肌的发生，并且过度表达 PASK会耗尽干细胞。因此，我们假设PASK在平衡自我更新与 再生过程中的分化。在这些数据的基础上，在本提案中，我们将研究如何 PASK的表达和活性在再生成肌细胞中受到调节（特异性目的1）。活化 MuSC，PASK磷酸化Wdr 5诱导H3 K4 me 3修饰，MyoD募集和核小体 Myog启动子上的重构，但其机制尚不清楚。在具体目标2中，我们将广泛 研究Wdr 5的两个相互作用的伴侣，其可以重塑Myog启动子以使其活化。后 诱导成肌蛋白，Pax 7表达下调，并建立终末分化。以来 PASK是Myog表达的上游调节因子，我们感兴趣的是确定如何损失或获得 PASK基因在再生和正常衰老过程中对自我更新种群的影响， 研究具体目标3。最终，这些目标将使我们了解利基信号线索如何控制 自我更新和分化之间的平衡，以及如何利用它来改善 生理状况，如肌肉减少症。