Post Translational Regulation of TET2 Function by Glucose Signaling

葡萄糖信号转导对 TET2 功能的翻译后调节

• 批准号: 9100886
• 负责人: Yujiang Geno Shi
• 金额: $ 33.73万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9100886
• 关键词: 5' -AMP-activated protein kinase; Affect; Binding Proteins; Biochemical; Biological; Biological Process; Cancer Cell Growth; Cell physiology; Cells; Coupled; Cues; Cytosine; DNA; DNA Methylation; DNA Methylation Regulation; Data; Diabetes Mellitus; Diet; Dioxygenases; Disease; Disease Progression; Down-Regulation; Drug Targeting; Environment; Enzymes; Epigenetic Process; Family; Gene Expression; Gene Silencing; Genes; Glucose; Goals; Health; Hexosamines; Homeostasis; Human; Hyperglycemia; Hypoglycemia; Indium; Life; Light; Link; Malignant Neoplasms; Maps; Mediating; Memory; Metabolic; Modification; Molecular; Nutrient; Outcome Study; Pathologic Processes; Pathway interactions; Pattern; Phenotype; Phosphorylation; Phosphoserine; Play; Positioning Attribute; Post-Translational Protein Processing; Post-Translational Regulation; Protein translocation; Proteins; Regulation; Reporting; Research; Resolution; Role; Serine; Signal Pathway; Signal Transduction; Solid; Sum; Technology; Therapeutic; Tumor Suppressor Proteins; UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase; base; cancer cell; embryonic stem cell; epigenome; genome-wide; glucose uptake; glycosylation; methylome; new therapeutic target; novel; novel therapeutics; organ growth; prevent; programs; promoter; prospective; protein function; response; treatment strategy; tumor growth; tumor progression

 DESCRIPTION (provided by applicant): DNA methylation at the 5 position of cytosine (5mC) is a critical epigenetic modification and plays key roles in various biological and pathological processes. The ten-eleven translocation (TET) families of dioxygenases primarily catalyze the conversion of 5mC to 5-hydroxymethylcytosine (5hmC). Several recent studies demonstrated that TET activities and the resultant 5hmC levels function as an epigenetic barrier for maintaining ES cell pluriopotency, governing organ development and preventing cancer progression. In particular, cancer cells have been shown to become more aggressive when TET gene expression or activity is compromised. These studies suggest that 5hmC and TET family proteins function as a checkpoint for cancer cell growth. For these reasons, investigating how TET proteins and 5hmC levels are regulated is necessary to fully understand how TET and 5hmC contribute to normal and pathological homeostasis. Based on solid preliminary data and the well-established deregulation of glucose uptake in cancer cells, we hypothesize that TET2 function is post-translationally regulated by distinctive post-translational modification (PTM), which can be modulated by glucose signaling. We further propose that the loss of the 5hmC tumor suppressor pathway in cancer cells is in part attributed to elevated glucose uptake and deregulated glucose signaling. The primary goal of this study is to understand how TET2 levels and activity are regulated by distinctive PTMs, which in turn impact on the TET2-controled DNA methylome/hydroxymethylome. Moreover, this proposal will unravel how protein-modifying enzymes differentially regulate TET2 PTMs in response to changes of glucose signaling. Specifically, in aim1 we will identify the cancer promoting changes to the hydorxymethylome/methylome that result from the deregulation of TET2 in response to aberrant glucose signaling, using the high resolution genome-wide mapping technologies we have developed. In aim 2&3, we will identify and characterize two types of glucose dependent PTMs observed on TET2, (glycosylation and phosphorylation), which are carried out by OGT and AMPK. Altogether, this proposal will characterize a novel regulatory circuit that maintains 5hmC levels through the posttranslational modifications of TET2 in response to glucose signaling. If successful, this proposal will significantly advance our understanding of the molecular mechanisms that facilitate cancer related changes at the epigenetic level in response to metabolic deregulation. This study will also establish a firm mechanistic link between changes in metabolic input to the adaption of the cancer epigenome. More importantly, identifying the molecular switch controlled by environmental cues that can turn on/off the 5hmC anti-tumor growth barrier in cancer will provide new therapeutic drug targeting strategies and treatments.

 描述（申请人提供）：DNA 胞嘧啶 5 位（5mC）甲基化是一种关键的表观遗传修饰，在各种生物和病理过程中发挥着关键作用。双加氧酶的 10-11 易位 (TET) 家族主要催化 5mC 转化为 5-羟甲基胞嘧啶 (5hmC)。最近的几项研究表明，TET 活性和由此产生的 5hmC 水平可作为表观遗传屏障，维持 ES 细胞多能性、控制器官发育和预防癌症进展。特别是，当 TET 基因表达或活性受到损害时，癌细胞会变得更具攻击性。这些研究表明 5hmC 和 TET 家族蛋白充当癌细胞生长的检查点。由于这些原因，有必要研究 TET 蛋白和 5hmC 水平的调节机制，以充分了解 TET 和 5hmC 如何促进正常和病理稳态。基于可靠的初步数据和癌细胞中葡萄糖摄取的失调，我们假设 TET2 功能受到独特的翻译后修饰 (PTM) 的翻译后调节，而这种修饰可以通过葡萄糖信号传导进行调节。我们进一步提出，癌细胞中 5hmC 肿瘤抑制途径的丧失部分归因于葡萄糖摄取增加和葡萄糖信号传导失调。本研究的主要目标是了解 TET2 水平和活性如何受到独特 PTM 的调节，进而影响 TET2 控制的 DNA 甲基化组/羟甲基化组。此外，该提案将揭示蛋白质修饰酶如何差异调节 TET2 PTM 以响应葡萄糖信号传导的变化。具体来说，在目标 1 中，我们将使用我们开发的高分辨率全基因组作图技术，确定因响应异常葡萄糖信号传导而导致 TET2 失调而导致的癌症促进羟甲基化组/甲基化组的变化。在目标 2 和 3 中，我们将鉴定并表征在 TET2 上观察到的两种类型的葡萄糖依赖性 PTM（糖基化和磷酸化），它们由 OGT 和 AMPK 进行。总而言之，该提案将描述一种新颖的调节回路，该回路通过响应葡萄糖信号传导的 TET2 翻译后修饰来维持 5hmC 水平。如果成功，该提议将显着增进我们对分子机制的理解，这些分子机制在表观遗传水平上促进癌症相关变化，以响应代谢失调。这项研究还将在代谢输入的变化与癌症表观基因组的适应之间建立牢固的机制联系。更重要的是，识别由环境线索控制的分子开关，可以打开/关闭癌症中的5hmC抗肿瘤生长屏障，将提供新的治疗药物靶向策略和治疗。