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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要最近的研究揭示了正常情况下通过替代启动子进行的普遍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、诊断或治疗方法仍未知。 Tet1 首次被确定为 AML 中的 MLL 伙伴。它属于春节（十 11 个易位）蛋白家族（Tet1/2 和 Tet3），将 5-甲基胞嘧啶 (5mC) 氧化成 5- 羟甲基胞嘧啶 (5hmC) 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TET1的一个短亚型（简称TET1-S），其中含有一个催化结构域但缺乏 N 端 CXXC 结构域，并且受替代启动子控制，在人类骨髓（BM）细胞。此外，TET1-S 在骨髓增生异常的 BM 细胞中表达上调综合征 (MDS) 患者与健康个体的比较。我们发现 TET1-S 在 BM 中表达与 TET1-F 相比，细胞水平要高得多。然而，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 在维持造血干细胞 (HSC) 及其上调通过破坏 HSC 和造血功能正常。为了检验这一假设，我们将确定 1) 致癌作用以及Tet1-S在MDS发病中的潜在机制，2）Tet1-S是否是MDS发病所必需的 MDS 的发展，3) Tet1-S 调节 HSPC 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来系统地分析 Tet1-S 过表达对 5mhC/mC 分布、染色质可及性和基因的渐进影响在造血干/祖细胞中表达。我们的工作将为 TET1-S 上调在 MDS 发病机制中的独特作用提供新的见解及其在维持 HSPC 的表观遗传景观和基因调控方面的具体作用和机制。