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.

（请保持言语，不要PDF）造血基因的正调可能导致功能专业血细胞产生的破坏。异常的DNA甲基化是造血中必不可少的关键表观遗传学特征，被认为是大多数血液损害的标志，包括骨髓增生性综合征（MDS）。不幸的是，当前批准的脱甲基剂对整个基因组无关紧要，并造成高毒性和低特异性的损失。因此需要实现选择性脱甲基化的策略。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中异常DNA甲基化。中心假设是造血中DNA甲基化的建立由专门的RNA控制，能够与DNA甲基转移酶1（DNMT1） - DNMT1-相互作用RNA（DIRS）结合。 DIR是宽度的，并以特异性方式预防DNA甲基化和沉默。具体而言，我们已经表明，造血分化的主要调节剂CCAAT/增强子结合蛋白α（CEBPA）在S相期间由Cebpa基因的Dir Originalized在S相的上游调节，称为额外编码（EC）CEBPA。该提案的总体目标是研究eCceBPA和谱系特定的DIR如何引导造血分化。该项目的理由是证明造血剂中DNA甲基化的DRA介导的调节。中心假设将通过追求两个具体目的来检验：1）定义eCceBPA在造血分化中的生物学作用； 2）定义DNMT1相互作用RNA在造血分化中的生物学作用。提出的研究具有创新性，因为我们将剖析造血分化中DNA甲基化的调节，并发现控制细胞类型特异性甲基化模式的机制。这很重要，因为我们将确定造血中DNA甲基化建立的关键表观遗传调节剂；并为转化方法奠定基础，以实现对这种临界表观遗传标记的基因特异性控制。