Structure and Functionof Nanog in Stem Cell Pluripotency

Nanog在干细胞多能性中的结构和功能

• 批准号: 10731813
• 负责人: Josephine Chu Ferreon
• 金额: $ 34.56万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731813
• 关键词: Adopted; Aging; Alleles; Behavior; Biochemical; Biological Assay; Biophysics; Cancer Relapse; Cells; Cellular biology; ChIP-seq; Chromatin; Chromatin Loop; Communication; DNA; DNA Binding; Dependence; Development; Differentiated Gene; Disease; Dominant-Negative Mutation; Dose; Elements; Epiblast; Epigenetic Process; Fluorescence; Fluorescence Recovery After Photobleaching; Fluorescence Resonance Energy Transfer; Funding; Genes; Genomics; Hi-C; Human; In Vitro; Investments; Lead; Link; Malignant Neoplasms; Mediating; Microscopy; Molecular; Molecular Probes; Mus; Nature; Peptides; Physical condensation; Play; Process; Property; Proteins; Reporting; Repression; Research Personnel; Resistance; Role; Source; Spectrum Analysis; Stem cell pluripotency; Structure; System; Techniques; Therapeutic; Time; Translating; Work; cancer stem cell; chemotherapy; cofactor; diagnostic biomarker; efficacy evaluation; embryonic stem cell; fluorescence imaging; fluorescence lifetime imaging; fortification; human embryonic stem cell; implantation; innovation; insight; novel; overexpression; pluripotency; prevent; prion-like; promoter; recruit; self assembly; self-renewal; single molecule; single-molecule FRET; transcription factor; tumor; tumor growth

Project Summary NANOG Structure and Function in Stem Cell Pluripotency NANOG directs access to stem cell pluripotency. There are considerable gaps in our molecular understanding of how NANOG coordinates this process. This is also compounded by the fact that NANOG (in particular, human NANOG) has been a challenging system to work with. The investigators have successfully applied innovative fluorescence techniques to characterize NANOG’s key structure and functional properties. NANOG is an intrinsically disordered protein (IDP), with a prion-like domain critical for NANOG self-assembly and for establishing contacts in pluripotency specific regions. NANOG is a ‘molecular hub’, reported to interact with >100 transcription factors (TFs) and other proteins to form cooperative hub condensates and coordinate activation of pluripotency genes and repression of differentiation genes. The investigators will investigate and deconvolute how NANOG dose-sensitivity play a role in chromatin looping and recruitment of TFs, co-activators, and epigenetic regulators. They will use an intensive holistic combination of standard and innovative structural, molecular, genomic and cell biology approaches. The first aim will elucidate NANOG’s dose-sensitivity mechanism in establishing pluripotency by assessing chromatin reorganization and recruitment of cofactors using Hi-C 3.0 and single molecule fluorescence techniques. The second aim will probe the molecular elements (i.e., OCT4-SOX2-NANOG triad cooperativity and KLF4 biomolecular condensation) involved in activating NANOG expression. In addition, the aim will investigate the molecular basis for NANOG autorepression. The last aim will focus on inhibition of NANOG stabilization and oligomerization with dominant negative NANOG-based peptides. These studies will provide unprecedented insights into how NANOG orchestrates establishment of stem cell pluripotency and reversal of developmental aging.

项目摘要 干细胞多能性的纳米结构和功能 NANOG指导进入干细胞多能。我们的空白很大 分子理解纳米如何协调这一过程。这也是由 Nanog（特别是人类Nanog）是工作的挑战系统，这一事实 和。研究人员已成功地将创新的荧光技术应用于 表征Nanog的关键结构和功能属性。 Nanog本质上是 无序蛋白质（IDP），具有对纳米自组装至关重要的prion样领域 在多能特定区域建立联系。 Nanog是一个“分子枢纽”，据报道 与> 100个转录因子（TFS）和其他蛋白质相互作用以形成合作中心 多能基因的冷凝和协调激活和分化的表达 基因。调查人员将调查并否定纳米剂量敏感性如何发挥 在TFS，共激活因子和表观遗传调节剂的染色质循环和募集中的作用。他们 将使用标准和创新结构的密集整体组合，分子， 基因组和细胞生物学方法。第一个目标将阐明Nanog的剂量敏感 通过评估染色质的重组和募集来建立多能性的机制 使用HI-C 3.0和单分子荧光技术的辅助因子。第二个目标 探测分子元素（即OCT4-SOX2-NANOG TRIAD协调和KLF4 生物分子冷凝）参与激活纳米表达。此外，目标将 研究Nanog自动压力的分子基础。最后一个目标将重点放在抑制上 纳米稳定和寡聚的基于负纳米的宠物。 这些研究将为Nanog如何策划建立提供前所未有的见解 干细胞多能性和发育衰老的逆转。

项目成果

Aggregation of Disordered Proteins Associated with Neurodegeneration.

• DOI: 10.3390/ijms24043380
• 发表时间: 2023-02-08
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

Micropolarized to the core.

微极化至核心。

• DOI: 10.1038/s41589-024-01542-3
• 发表时间: 2024
• 期刊: Nature chemical biology
• 影响因子: 14.8
• 作者: Quan,MyDiem;Ferreon,JosephineC;Ferreon,AllanChrisM
• 通讯作者: Ferreon,AllanChrisM

NANOG prion-like assembly mediates DNA bridging to facilitate chromatin reorganization and activation of pluripotency.

• DOI: 10.1038/s41556-022-00896-x
• 发表时间: 2022-05
• 期刊: Nature cell biology
• 影响因子: 21.3

Fluorescence Lifetime Imaging Microscopy of Biomolecular Condensates.

• DOI: 10.1007/978-1-0716-2663-4_6
• 发表时间: 2023
• 期刊: Methods in molecular biology (Clifton, N.J.)

Synthesis, Structure-Activity Relationships, and Antiviral Activity of Allosteric Inhibitors of Flavivirus NS2B-NS3 Protease.

• DOI: 10.1021/acs.jmedchem.0c02070
• 发表时间: 2021-03-11
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Nie S;Yao Y;Wu F;Wu X;Zhao J;Hua Y;Wu J;Huo T;Lin YL;Kneubehl AR;Vogt MB;Ferreon J;Rico-Hesse R;Song Y
• 通讯作者: Song Y