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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.

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