Regulation of Transcription Elongation in Adipose Homeostasis

脂肪稳态中转录伸长的调节

• 批准号: 10062963
• 负责人: Lily Q Dong
• 金额: $ 45.83万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062963
• 关键词: Ablation; Adipocytes; Adipose tissue; Adverse effects; Biochemical; Biological; Biology; Brown Fat; Cell Culture System; Cell physiology; Cells; Clinical; Complement; Country; Cues; DNA Polymerase II; DNA-Directed RNA Polymerase; Data; Databases; Diabetes Mellitus; Diet; Endocrine; Epidemic; Exhibits; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Models; Genetic Transcription; Genomics; Health; Homeostasis; Human; Impairment; Investigation; Knock-out; Laboratories; Maintenance; Malignant Neoplasms; Mediating; Metabolic; Metabolic Diseases; Modeling; Molecular; Mus; Obesity; Pathway interactions; Physiological; Play; Positioning Attribute; Pre-Clinical Model; Regulation; Research; Role; Sampling; Scientist; Stromal Cells; System; Technology; Testing; Thermogenesis; Time; Tissues; Transcription Elongation; Transcription Initiation; Transcription Initiation Site; Transcriptional Activation; Transcriptional Regulation; Weight Gain; Work; base; bioinformatics tool; experimental study; human disease; improved; innovation; insight; lipid biosynthesis; mouse genetics; mouse model; multidisciplinary; negative elongation factor; novel; overexpression; programs; promoter; recruit; response; stem cells; tool; transcription factor; virtual

For genes involved in tissue generation and homeostasis, RNA polymerase II (Pol II) tends to pause immediately downstream of their transcription start sites. Compared to de novo recruitment of Pol II, a preassembled and poised Pol II could be more conducive to rapid and synchronous transcriptional activation in response to various physiologic cues. However, virtually nothing is known about the biological significance of this highly conserved and prevalent phenomenon in transcriptional regulation of tissue generation and homeostasis. We recently observed that many known adipogenic genes exhibit Pol II pausing. We also found that adipose tissue-specific ablation of a key Pol II-pausing factor, NELF, results in impaired white adipogenesis but elevated expression of genes involved in beige adipose thermogenesis. In the current proposal, we will test the central hypothesis that NELF-mediated Pol II pausing plays a dual function in white adipose tissue (WAT) homeostasis: it promotes differentiation of adipose progenitor cells to mature white adipocytes, and suppresses white-to-beige inter-conversion. Our multidisciplinary team of laboratory and clinician scientists will use mouse genetics, cell culture systems, and clinical samples to test this innovative hypothesis. We will first use murine and clinical samples to determine the cellular function of NELF in WAT establishment and maintenance. We will then use new mouse genetic models to evaluate the role of NELF in beige adipose thermogenesis. Lastly, we will combine target-gene approaches and genomic/bioinformatics tools to interrogate NELF-dependent Pol II pausing and transcriptional regulation in adipose homeostasis. The novel concept we seek to validate in our proposed work clearly departs from the prevailing transcription initiation-centric paradigm in adipose gene regulation. In particular, the new Pol II pausing-dependent mechanism points to a previously unappreciated direction for elucidating the transcriptional network that regulates adipose homeostasis. When successfully executed, our studies, underpinned by extensive preliminary data, promise to yield new insights into obesity-related metabolic diseases.

对于参与组织生成和稳态的基因，RNA 聚合酶 II (Pol II) 往往会在其转录起始位点下游立即暂停。与 Pol II 的从头招募相比，预组装和平衡的 Pol II 可能更有利于快速同步转录激活，以响应各种生理信号。然而，对于组织生成和稳态的转录调控中这种高度保守和普遍的现象的生物学意义，实际上一无所知。我们最近观察到许多已知的脂肪形成基因表现出 Pol II 暂停。我们还发现，脂肪组织特异性消融关键的 Pol II 暂停因子 NELF，会导致白色脂肪生成受损，但参与米色脂肪产热的基因表达升高。在当前的提案中，我们将测试中心假设，即 NELF 介导的 Pol II 暂停在白色脂肪组织 (WAT) 稳态中发挥双重功能：它促进脂肪祖细胞分化为成熟的白色脂肪细胞，并抑制白色脂肪细胞向米色脂肪细胞的分化。相互转换。我们的实验室和临床科学家多学科团队将使用小鼠遗传学、细胞培养系统和临床样本来测试这一创新假设。我们将首先使用小鼠和临床样本来确定 NELF 在 WAT 建立和维持中的细胞功能。然后，我们将使用新的小鼠遗传模型来评估 NELF 在米色脂肪生热作用中的作用。最后，我们将结合靶基因方法和基因组/生物信息学工具来探究脂肪稳态中 NELF 依赖性 Pol II 暂停和转录调控。我们试图在我们提出的工作中验证的新概念显然偏离了脂肪基因调控中普遍存在的以转录起始为中心的范式。特别是，新的 Pol II 暂停依赖性机制为阐明调节脂肪稳态的转录网络指明了一个以前未被重视的方向。如果成功执行，我们的研究将以大量初步数据为基础，有望对肥胖相关代谢疾病产生新的见解。

项目成果

BRCA1 Antibodies Matter.

BRCA1 抗体很重要。

• 发表时间: 2021
• 作者: Yang, Jing;Qi, Leilei;Chiang, Huai;Yuan, Bin;Li, Rong;Hu, Yanfen
• 通讯作者: Hu, Yanfen

Epithelial NELF guards intestinal barrier function to ameliorate colitis by maintaining junctional integrity.

上皮 NELF 通过维持连接完整性来保护肠道屏障功能，从而改善结肠炎。

• 发表时间: 2022-02
• 影响因子: 8
• 作者: Ou, Jiayao;Guan, Xiaoxing;Wang, Jiali;Wang, Tianjiao;Zhang, Bin;Li, Rong;Xu, Huji;Hu, Xiaoyu;Guo, Xue
• 通讯作者: Guo, Xue