Transcription regulation in chromatin

染色质的转录调控

• 批准号: 10544298
• 负责人: JERRY L WORKMAN
• 金额: $ 42.49万
• 依托单位: STOWERS INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544298
• 关键词: ARID1A gene; ATP phosphohydrolase; Acetylation; Affect; Bromodomain; Cancer cell line; Cell Cycle Progression; Cell physiology; Cellular Metabolic Process; Chromatin; Chromatin Remodeling Factor; Complex; Development; Disease; Gene Activation; Genes; Genetic Transcription; Goals; Histones; Homeostasis; Human; Malignant Neoplasms; Mammalian Cell; Mammals; Metabolism; Methylation; Methyltransferase; Modification; Mutation; Nucleosomes; Oxidation-Reduction; Pathway interactions; Phospholipid Metabolism; Phosphorylation; Phosphotransferases; Protein Biosynthesis; Proteins; RNA Processing; RNA Splicing; Recurrence; Regulation; Regulon; Ribonucleoproteins; Role; SMARCA2 gene; SMARCA4 gene; SWI/SNF Family Complex; Signal Pathway; Signal Transduction; Stress; Sulfur Amino Acids; Therapeutic; Transcriptional Regulation; Tumor Suppressor Proteins; Yeasts; amino acid metabolism; detection of nutrient; histone methylation; interest; novel; paralogous gene; particle; protein function; response; transcription factor

Project Summary The goals of this proposal are to investigate fundamental mechanisms of chromatin modifiers which, when perturbed, may create conditions that can lead to cancer and other diseases in humans. These studies will largely focus on chromatin remodeling complexes (e.g. Swi/Snf) and proteins which modify histones (e.g. methylation, phosphorylation) in response to transcription, cell signaling and metabolism. The Swi/Snf nucleosome-remodeling complex functions as a tumor suppressor. Recurrent mutations in Swi/Snf are found in many cancers. This proposal focuses on novel functions of Swi/Snf complexes in yeast and mammalian cells that may contribute to cancer development when lost. Many subunits of the mammalian Swi/Snf complex have alternative paralog subunits which occupy different versions. Importantly, depletion of multiple paralogs of specific subunits has been shown to be synthetic lethal in cancer cell lines suggesting potential therapeutic avenues. We will investigate the redundant and nonredundant functions of paralogous subunits starting with ARID1A/ARID1B and SMARCA2/SMARCA4 (alternative ATPase subunits). We have found that ARID1B (but not ARID1A) interacts with paraspeckle (ribonucleoprotein particle) components and regulates splicing. We will explore the mechanisms and functions of Swi/Snf interactions with paraspeckles. We have discovered that SMARCA2 bromodomain undergoes acetylation unlike its paralog SMARCA4. We will investigate how this modification affects the activities of SMARCA2-containing Swi/Snf complexes including their interactions with acetylated nucleosomes. In yeast we have found that Swi/Snf regulates a number of genes involved in sulfur amino acid metabolism (The MET regulon). We will investigate the role of Swi/Snf in controlling the transcription factor Met4 and the MET regulon in general which is of particular interest due to the role of Met4 and the MET regulon in regulating cellular processes such as redox homeostasis, methylation, phospholipid metabolism, protein synthesis and cell cycle progression. Our discovery that the mammalian SETD2 methyltransferase interacts with RNA processing proteins (e.g. hnRNPL) has led us to investigate how these interactions regulate histone methylation during transcription and RNA splicing and processing. Finally, in yeast we discovered a nutrient sensing signaling pathway combining the CK2 and AMPK pathways to converge on the Tda1 kinase which phosphorylates histone H3T11 and activates stress responsive genes. Proposed studies will investigate regulation of Tda1, the functions of H3T11 phosphorylation in gene activation and whether this nutrient sensing pathway is conserved in mammals.

项目摘要 该提案的目标是研究染色质修饰符的基本机制 当受到干扰时，可能会产生可能导致癌症和其他疾病的疾病 人类。这些研究将主要集中在染色质重塑络合物（例如SWI/SNF）和 蛋白质（例如甲基化，磷酸化）响应转录， 细胞信号传导和代谢。 SWI/SNF核小体复制复合物充当 肿瘤抑制剂。在许多癌症中发现了SWI/SNF中的复发突变。这个建议 专注于酵母和哺乳动物细胞中SWI/SNF复合物的新功能 丢失时会导致癌症发展。哺乳动物SWI/SNF综合体的许多亚基 具有占有不同版本的替代旁系同源亚基。重要的是，耗尽 特定亚基的多个旁系同源物已显示在癌细胞系中是合成的致命 暗示潜在的治疗途径。我们将研究冗余和非冗余 以ARID1A/ARID1B和SMARCA2/SMARCA4开头的寄生亚基的功能 （替代ATPase亚基）。我们发现Arid1b（而不是ARID1A）与 （核糖核蛋白颗粒）成分并调节剪接。我们将探索 SWI/SNF与拼贴相互作用的机制和功能。我们发现 Smarca2溴化域经历乙酰化，与旁系同源物Smarca4不同。我们将 研究这种修改如何影响含Smarca2的SWI/SNF的活动 复合物，包括它们与乙酰化核小体相互作用。在酵母中，我们发现 SWI/SNF调节许多参与硫氨基酸代谢的基因（Met Regulon）。我们将研究SWI/SNF在控制转录因子Met4和 大都会法规通常是由于MET4和MET的作用而特别感兴趣的 调节细胞过程（例如氧化还原稳态，甲基化，磷脂）中的调节子。 代谢，蛋白质合成和细胞周期进程。我们发现哺乳动物 SetD2甲基转移酶与RNA加工蛋白（例如HNRNPL）相互作用已导致我们进入 研究这些相互作用在转录和RNA期间如何调节组蛋白甲基化 剪接和处理。最后，在酵母中，我们发现了一种营养感应信号通路 将CK2和AMPK途径组合在TDA1激酶上，该途径磷酸化的TDA1激酶 组蛋白H3T11并激活应力响应基因。拟议的研究将调查 调节TDA1，H3T11磷酸化在基因激活中的功能以及是否是否 营养感应途径在哺乳动物中是保守的。