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，通过正常的替代启动子进行普遍的转录调控 组织和癌症。大多数替代启动子如何促进肿瘤形成，诊断或 治疗仍然未知。 TET1首先被确定为AML中的MLL合作伙伴。它属于tet（十 - 蛋白质（TET1/2和TET3）家族，将5-甲基胞嘧啶（5MC）氧化为5-- 羟基环霉素（5HMC）和其他OXI-MC中间体，从而促进DNA脱甲基化。 有趣的是，我们发现TET1的简短同工型（称为TET1-S），其中包含一个催化域 但是缺乏N末端CXXC结构域，并且在替代启动子的控制中被表达 人骨髓（BM）细胞。另外，从骨髓增生的BM细胞中TET1-S上调 与健康个体相比，综合征（MDS）患者。我们表明TET1-S在BM中表达 与TET1-F相比，细胞水平更高。但是，其在造血系统中的作用尚不清楚。 根据我们的初步结果，我们假设TET1-S在维持中起着重要作用 造血干细胞（HSC）及其上调通过破坏MD的发展有助于 HSC和造血的正常功能。为了检验这一假设，我们将确定1）致癌作用 TET1-S在MDS发病机理中的潜在机制，2）2）是否需要TET1-S MDS的开发和3）TET1-S调节基因表达HSPCS的分子机制 和红细胞祖细胞。我们将采用多种基因组方法系统地分析 TET1-S过表达对5MHC/MC分布，染色质可及性和基因的逐步影响 造血干/祖细胞中的表达。 我们的工作将为TET1-S上调在MD的发病机理中的独特作用提供新的见解 以及其在HSPC中维持表观遗传景观和基因调节中的特定作用和机制。