Role of the TET1 short isoform in MDS development and maintenance

TET1 短亚型在 MDS 开发和维护中的作用

• 批准号: 10552668
• 负责人: Zhijian Qian
• 金额: $ 53.55万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-20 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10552668
• 关键词: APC gene; ATAC-seq; Acute Erythroblastic Leukemia; Acute T Cell Leukemia; Affect; Anemia; B-Cell Lymphomas; Binding; Bone Marrow Cells; CD34 gene; Catalytic Domain; Cell Differentiation process; Cells; ChIP-seq; Chromatin; DNA; DNA Methylation; Development; Diagnosis; Disease; Distal; Down-Regulation; Dysmyelopoietic Syndromes; EVI1 gene; Ectopic Expression; Enhancers; Epigenetic Process; Erythroblasts; Erythroid Progenitor Cells; Erythropoiesis; Gene Expression; Gene Expression Regulation; Genes; Genomic approach; Hematology; Hematopoiesis; Hematopoietic System; Hematopoietic stem cells; Hemin; Human; In Vitro; Individual; Ineffective Hematopoiesis; K562 Cells; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Molecular; Mus; Myelogenous; Myeloid Leukemia; N-terminal; Normal tissue morphology; Nucleic Acid Regulatory Sequences; Oncogenes; Oncogenic; Pathogenesis; Pathway interactions; Patients; Pattern; Play; Proliferating; Protein Family; Protein Isoforms; Regulatory Element; Role; Stretching; Testing; Transcriptional Regulation; Transgenic Mice; Tumor Suppressor Genes; Tumor Suppressor Proteins; Up-Regulation; WNT Signaling Pathway; Work; Xenograft procedure; acute lymphoblastic leukemia cell; beta catenin; demethylation; erythroid differentiation; hematopoietic stem cell self-renewal; in vivo; insight; knock-down; leukemia; mouse model; overexpression; promoter; stem cell function; transcriptome; transcriptome sequencing; transgene expression; tumor

PROJECT SUMMARY Recent studies have revealed pervasive transcriptional regulation through alternative promoters in normal tissues and cancer. How the majority of alternative promoters contribute to tumor formation, diagnosis or treatment remains unknown. Tet1 was first identified as an MLL partner in AML. It belongs to the Tet (ten- eleven translocation) family of proteins (Tet1/2 and Tet3), which oxidize 5-methylcytosine (5mC) into 5- hydroxymethylcytosine (5hmC), and other oxi-mC intermediates, thereby facilitating DNA demethylation. Interestingly, we found that a short isoform of TET1 (referred to as TET1-S), which contains a catalytic domain but lacks the N-terminal CXXC domain, and is under control of an alternative promoter, was expressed in human bone marrow (BM) cells. Additionally, TET1-S was upregulated in BM cells from Myelodysplastic Syndrome (MDS) patients as compared to healthy individuals. We showed that TET1-S is expressed in BM cells at a much higher level compared with TET1-F. However, its role in the hematopoietic system is unknown. Based on our preliminary results, we hypothesize that Tet1-S plays an important role in the maintenance of hematopoietic stem cells (HSCs) and its upregulation contributes to the development of MDS by disrupting normal function of HSCs and hematopoiesis. To test this hypothesis, we will determine 1) the oncogenic role and underlying mechanisms of Tet1-S in the pathogenesis of MDS, 2) whether Tet1-S is required for the development of MDS, and 3) the molecular mechanisms by which Tet1-S regulates gene expression in HSPCs and erythroid progenitor cells. We will employ multiple genomic approaches to systematically analyze the progressive effects of Tet1-S overexpression on 5mhC/mC distribution, chromatin accessibility and gene expression in hematopoietic stem/progenitor cells. Our work will provide new insights into the distinct role of TET1-S upregulation in the pathogenesis of MDS as well as its specific role and mechanisms in maintaining epigenetic landscapes and gene regulation in HSPCs.

项目摘要 最近的研究表明，在正常的细胞中，通过替代启动子进行广泛的转录调控。 组织和癌症。大多数替代启动子如何促进肿瘤形成，诊断或治疗 治疗仍然未知。Tet 1最初被确定为AML中的MLL伙伴。它属于泰特（十- 十一易位）蛋白质家族（Tet 1/2和Tet 3），其将5-甲基胞嘧啶（5 mC）氧化成5-甲基胞嘧啶（5 mC）。 羟甲基胞嘧啶（5 hmC）和其他oxi-mC中间体，从而促进DNA去甲基化。 有趣的是，我们发现TET 1的一个短的同种型（称为TET 1-S），它包含一个催化结构域， 但缺乏N-末端CXXC结构域，并在另一个启动子的控制下，在 人骨髓（BM）细胞。此外，TET 1-S在骨髓增生异常的BM细胞中上调， 综合征（MDS）患者与健康个体相比。我们发现TET 1-S在BM中表达， 与TET 1-F相比，TET 1-F细胞的水平更高。然而，其在造血系统中的作用尚不清楚。 基于我们的初步结果，我们假设Tet 1-S在维持细胞凋亡中起重要作用。 造血干细胞（HSC）及其上调通过破坏造血干细胞（HSC）的增殖和分化而促进MDS的发展。 造血干细胞和造血功能正常。为了验证这一假设，我们将确定1）致癌作用 Tet 1-S在MDS发病机制中的潜在机制，2）Tet 1-S是否是MDS发病所必需的， Tet 1-S调控HSPCs基因表达的分子机制 和红系祖细胞。我们将采用多种基因组方法系统地分析 Tet 1-S过表达对5 mhC/mC分布、染色质可及性和基因表达的进行性影响 在造血干/祖细胞中表达。 我们的工作将为TET 1-S上调在MDS发病机制中的独特作用提供新的见解， 以及其在维持HSPCs表观遗传景观和基因调控中的特定作用和机制。