Understanding the role of cell-cycle specific RNAs in hematopoiesis

了解细胞周期特异性 RNA 在造血中的作用

基本信息

批准号：
10518484
负责人：
Annalisa Di Ruscio
金额：
$ 34.58万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
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：
2022-09-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10518484
关键词：
Aberrant DNA Methylation Autoimmune Diseases Automobile Driving Binding Biological Biological Assay Blood Cells Bone Marrow CCAAT-Enhancer-Binding Protein-alpha Cell Cycle Cells Code DNA Methylation DNA Methylation Regulation DNA Modification Methylases Data Development Disease Down-Regulation Dysmyelopoietic Syndromes Epigenetic Process Foundations Future Generations Genes Goals Guide RNA Hematologic Neoplasms Hematopoiesis Hematopoietic Hematopoietic Neoplasms Hematopoietic System Human In Vitro Individual Knowledge Lead Malignant Neoplasms Maps Mediating Methods Methylation Molecular Mononuclear Muscle Myelogenous Neurons Oligonucleotides Outcome Pathologic Play Process Production Public Health RNA Research Role S phase Sampling Specificity Testing Time Tissues Toxic effect Transcript Transcriptional Regulation Variant cell type clinical application demethylation evidence base gain of function genome-wide genomic locus granulocyte hematopoietic differentiation hematopoietic gene innovation methylation pattern nervous system disorder prevent programs targeted treatment tool whole genome

项目摘要

(PLEASE KEEP IN WORD, DO NOT PDF) Misregulation of hematopoietic genes can result in disruption of the production of functionally specialized blood cells. Abnormal DNA methylation, a key epigenetic signature essential in hematopoiesis, is regarded as the hallmark of most hematological malignancies, including myelodysplastic syndromes (MDS). Unfortunately, the currently approved demethylating agents act indiscriminately on the entire genome and come with a toll of high toxicity and low specificity. Strategies to achieve selective demethylation are therefore needed. The long-term goal of our research is to understand how to develop a highly specific and low toxic approach to correct aberrant DNA methylation in disease states. The central hypothesis is that the establishment of DNA methylation in hematopoiesis is controlled by specialized RNAs, able to bind to the DNA methyltransferase 1 (DNMT1) – DNMT1- interacting RNAs (DiRs). DiRs are widespread and prevent DNA methylation and silencing in a locus-specific manner. Specifically, we have shown that the expression of a master regulator of hematopoietic differentiation, CCAAT/enhancer-binding protein alpha (CEBPA), is regulated by a DiR originated upstream of the CEBPA gene during the S phase, termed extra-coding (ec)CEBPA. The overall objectives of this proposal are to investigate how ecCEBPA and lineage specific DiRs guide hematopoietic differentiation. The rationale for this project is to demonstrate DiR-mediated regulation of DNA methylation in hematopoiesis. The central hypothesis will be tested by pursuing two specific aims: 1) Define the biological role of ecCEBPA in hematopoietic differentiation; and 2) Define the biological role of DNMT1-interacting RNAs in hematopoietic differentiation. The proposed research is innovative because we will dissect the regulation of DNA methylation in hematopoietic differentiation and uncover the mechanisms underlying the control of cell type-specific methylation patterns. It is significant because we will identify key epigenetic regulators governing the establishment of DNA methylation in hematopoiesis; and lay the foundation for a transformative approach to achieve gene-specific control of this critical epigenetic mark.

（请以 WORD 形式保存，请勿以 PDF 形式保存）造血基因的失调可能会导致功能特化血细胞的产生受到破坏，DNA 甲基化是造血过程中必需的关键表观遗传特征，被认为是大多数血液恶性肿瘤的标志，包括骨髓增生异常综合征 (MDS)。已批准的去甲基化剂不加区别地作用于整个基因组，并且具有高毒性和低特异性，因此需要采取策略来实现选择性去甲基化。我们研究的长期目标是了解如何开发一种高度特异性和低毒性的方法来纠正疾病状态下的异常 DNA 甲基化，核心假设是造血过程中 DNA 甲基化的建立是由专门的 RNA 控制的。能够结合 DNA 甲基转移酶 1 (DNMT1) – DNMT1 相互作用 RNA (DiR) 广泛存在，并以位点特异性方式防止 DNA 甲基化和沉默。，我们已经证明造血分化的主调节因子 CCAAT/增强子结合蛋白 α (CEBPA) 的表达在 S 期期间受到起源于 CEBPA 基因上游的 DiR 的特异性调节，称为额外编码 (ec) CEBPA。该提案的总体目标是研究 ecCEBPA 和谱系特异性 DiR 如何指导造血分化。该项目的基本原理是证明 DiR 介导的 DNA 调节。我们将通过两个具体目标来检验中心假设：1) 定义 ecCEBPA 在造血分化中的生物学作用；2) 定义 DNMT1 相互作用的 RNA 在造血分化中的生物学作用。我们将剖析 DNA 甲基化在造血分化中的调控，并揭示细胞类型特异性甲基化模式控制的机制，这一点意义重大。我们将确定造血过程中 DNA 甲基化建立的关键表观遗传调控因子，并为实现这一关键表观遗传标记的基因特异性控制的变革方法奠定基础。