Molecular Mechanism of TET-mediated Gene Regulation

TET介导的基因调控的分子机制

• 批准号: 10714155
• 负责人: Chan-Wang Jerry Lio
• 金额: $ 38.36万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714155
• 关键词: Aberrant DNA Methylation; Acute; Animal Model; Biological Process; Cell Differentiation process; Chromatin; Cytosine; DNA; DNA Methylation; DNA Modification Process; Disease; Elements; Enhancers; Ensure; Environment; Enzymes; Epigenetic Process; Family; Gene Activation; Gene Expression; Gene Expression Regulation; Genes; Genomic Instability; Goals; Health; Hematologic Neoplasms; Hematopoietic Neoplasms; Histones; Human; Immunodeficiency and Cancer; Link; Maintenance; Malignant Childhood Neoplasm; Malignant Neoplasms; Mammalian Cell; Maps; Mediating; Methods; Methylation; Modification; Molecular; Monitor; Mutate; Mutation; Research; demethylation; epigenome; epigenome editing; insight; methylation pattern; methylome; novel; permissiveness; programs; therapeutic target

PROJECT SUMMARY/ABSTRACT DNA cytosine methylation is a central epigenetic modification in mammalian cells. Aberrant DNA methylation has been linked to gene dysregulation and genomic instability, resulting in cancer and other diseases. Ten- Eleven Translocation (TET) is the essential enzyme family responsible for DNA demethylation to ensure the proper maintenance of the methylome. TET enzymes oxidize 5-methylcytosines (5mC) into mainly 5- hydroxymethylcytosine (5hmC), an intermediate for DNA demethylation and a potential epigenetic mark. Germline deficiency of TET2 is associated with immunodeficiency and childhood cancers. Notably, TET2 is one of the most frequently mutated genes in hematological cancers, demonstrating the importance of TET in multiple biological processes. We and others have shown that TET enzymes are essential for cell differentiation by regulating super-enhancers and inducing the expression of lineage-specific genes. However, the mechanism by which TET enzymes facilitate the permissive chromatin environment for gene activation remains unclear. The long-term goals of the research program are: (1) to comprehensively understand how TET enzymes and 5hmC promote chromatin accessibility; (2) to investigate the crosstalk between TET and histones; (3) to understand the consequences of temporary perturbation of epigenome. To accomplish these goals, we will use precision epigenome editing to manipulate and monitor epigenetic modifications of cis- elements regulated by TET and DNA methylation. We will develop novel animal models to study the impact of acute and reversible TET deficiency and a sequencing method to map multiple DNA modifications and chromatin accessibility simultaneously on a single DNA molecule. Our research will provide crucial mechanistic insights into how TET and DNA modifications regulate gene expression and cell differentiation. Our findings will potentially identify genes involved in immunodeficiency and cancer, providing an opportunity to develop targeted treatments.

项目概要/摘要 DNA 胞嘧啶甲基化是哺乳动物细胞中的重要表观遗传修饰。 DNA甲基化异常 与基因失调和基因组不稳定有关，导致癌症和其他疾病。十- 十一易位 (TET) 是负责 DNA 去甲基化的重要酶家族，以确保 甲基化组的适当维护。 TET 酶将 5-甲基胞嘧啶 (5mC) 氧化成主要为 5- 羟甲基胞嘧啶 (5hmC)，DNA 去甲基化的中间体和潜在的表观遗传标记。 TET2 种系缺陷与免疫缺陷和儿童癌症有关。值得注意的是，TET2 是 血液癌症中最常见的突变基因之一，证明了 TET 在血液癌症中的重要性 多种生物过程。我们和其他人已经证明 TET 酶对于细胞至关重要 通过调节超级增强子和诱导谱系特异性基因的表达来分化。然而， TET 酶促进基因激活的允许染色质环境的机制 仍不清楚。研究计划的长期目标是：（1）全面了解如何 TET 酶和 5hmC 促进染色质可及性； (2) 研究TET和之间的串扰 组蛋白； (3)了解表观基因组暂时扰动的后果。为了完成这些 目标，我们将使用精确的表观基因组编辑来操纵和监测顺式的表观遗传修饰 受 TET 和 DNA 甲基化调节的元件。我们将开发新的动物模型来研究的影响 急性和可逆的 TET 缺陷以及绘制多个 DNA 修饰图谱的测序方法 染色质可同时在单个 DNA 分子上进行可及性。我们的研究将提供关键的机制 深入了解 TET 和 DNA 修饰如何调节基因表达和细胞分化。我们的发现 将有可能识别出与免疫缺陷和癌症有关的基因，从而提供开发机会 有针对性的治疗。