A Myc-centered network in embryonic stem cells and somatic cell reprogramming

胚胎干细胞和体细胞重编程中以 Myc 为中心的网络

• 批准号: 8306706
• 负责人: Jonghwan Kim
• 金额: $ 24.51万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-03 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8306706
• 关键词: Address; Animals; Area; Cell Maintenance; Cells; Chromatin Structure; Chromosome Structures; Chromosomes; Complex; Data; Development; Ectopic Expression; Epigenetic Process; Future; Generations; Genetic Transcription; Goals; Histone Acetylation; Instruction; Knowledge; Malignant Neoplasms; Mediating; Medicine; Mentors; Molecular; Oncogenic; Patients; Phase; Pluripotent Stem Cells; Procedures; Process; Proteins; Publishing; Regenerative Medicine; Research; Resources; Role; Science; Somatic Cell; Techniques; Testing; Therapeutic; Tumorigenicity; Work; adult stem cell; embryonic stem cell; flexibility; genome-wide; histone acetyltransferase; histone modification; induced pluripotent stem cell; interest; pluripotency; protein complex; self-renewal; stem cell therapy; stemness; transcription factor

Pluripotent stem cells, such as ES cells and induced pluripotent stem cells (IPS cells) are important for their therapeutic potential in regenerative medicine, and it has been suggested that many transcription regulators are critical for their stemness (self-renewal and pluripotency) control. Myc is one of the four transcription factors (Oct4, Sox2, Klf4, and Myc) used in generation of IPS cells and is a protein of interest due to its dual roles in the reprogramming process; reactivation of Myc in the chimeric animals generated by IPS cells showed increased tumorigenicity, but in the absence of Myc, the efficiency of iPS cell generation was reduced by several hundred fold. These observations clearly imply the critical roles of Myc in facilitating direct reprogramming process, however the molecular mechanisms of Myc in this process have not been addressed. Our recent work suggests that Myc has many interacting partner proteins in ES cells including co-factors in NuA4 histone acetyltransferase complex (NuA4 HAT complex). Previous studies showed that histone acetylation signature is involved in chromosome decondensation. Since the chromatin structure of ES cells is hyperdynamic and flexible compared to the chromosomal structure of differentiated cells, we propose that the function of Myc in ES cells or somatic cell reprogramming may be mediated by the interaction partner proteins of Myc including histone acetyltransferases. To further understand molecular mechanisms of Myc and its interacting partner proteins, I propose the following Specific Aims: 1) Identification of epigenetic signatures involved in the function ofthe Myc-centered network in ES cells. 2) Testing somatic cell reprogramming potential of each factor in Myc-centered regulatory network during IPS cell generation. :. The goals of this proposal are to understand the molecular mechanisms ofthe Myc-centered regulatory network in pluripotent stem cells and to develop alternative ways of efficient generation of iPS cells without oncogenic Myc.

多能干细胞，如ES细胞和诱导多能干细胞(IPS细胞)对 它们在再生医学中的治疗潜力，并已被认为是许多转录 监管机构对它们的主干(自我更新和多能性)控制至关重要。MYC是四家公司之一 转录因子(Oct4、Sox2、Klf4和Myc)用于IPS细胞的生成，是一种感兴趣的蛋白质 由于其在重新编程过程中的双重作用；Myc在由 IPS细胞显示出更高的致瘤性，但在没有Myc的情况下，iPS细胞的生成效率 减少了几百倍。这些观察结果清楚地暗示了Myc在促进 直接重编程过程，然而Myc在这一过程中的分子机制尚未得到研究 地址。我们最近的工作表明，Myc在ES细胞中有许多相互作用的伙伴蛋白，包括 NuA4组蛋白乙酰转移酶复合体(NuA4 HAT复合体)的辅助因子。此前的研究表明， 组蛋白乙酰化信号与染色体解缩有关。由于染色质的结构 与分化细胞的染色体结构相比，ES细胞是高度活跃和灵活的，我们 提示Myc在ES细胞或体细胞重编程中的作用可能是通过 Myc的相互作用伙伴蛋白包括组蛋白乙酰转移酶。 为了进一步了解Myc及其相互作用的伙伴蛋白的分子机制，我提出了 具体目标如下：1)鉴定与Myc为中心的功能有关的表观遗传学特征 在胚胎干细胞中的网络。2)以Myc为中心检测各因子的体细胞重编程潜能 在IPS细胞生成过程中的调控网络。：。 这项建议的目的是了解以Myc为中心的调控的分子机制 在多能干细胞中建立网络，并开发高效产生iPS细胞的替代方法，而不需要 致癌霉菌。