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The role of ALKBH5-mediated RNA demethylation in the maintenance of genomic stability in HSPCs

ALKBH5 介导的 RNA 去甲基化在维持 HSPC 基因组稳定性中的作用

基本信息

批准号：
10445661
负责人：
Zhijian Qian
金额：
$ 47.85万
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：
2022-09-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10445661
关键词：
Aging Apoptosis Biological Process CD34 gene Cell Death Cell Maintenance Cells Chromatin DNA Damage DNA Repair DNA lesion Development Dysmyelopoietic Syndromes Functional disorder Gene Expression Gene Expression Regulation Genetic Transcription Genome Stability Genomic Instability Goals Growth Hematological Disease Hematopoietic Hematopoietic stem cells Histone Deacetylase Human Human Cell Line In Vitro Life Long-Term Effects Maintenance Malignant - descriptor Malignant Neoplasms Mediating Mediator of activation protein Messenger RNA Methylation Modeling Modification Molecular Mus Mutagenesis Oncogene Activation Oncogenes Oxidative Stress Pathway interactions Patients Phenocopy Physiological Play Polyribosomes Post-Transcriptional Regulation Post-Translational Protein Processing Process RNA RNA methylation Reactive Oxygen Species Role Source Speed Stem Cell Development Stress System Testing Time Transgenic Mice Transgenic Organisms Up-Regulation Xenograft procedure cell injury crosslinking and immunoprecipitation sequencing demethylation epigenetic regulation genome integrity hematopoietic stem cell self-renewal in vivo insight knock-down leukemic transformation novel novel therapeutic intervention overexpression prevent repaired response ribosome profiling self-renewal stem cell function stem cells transcriptome sequencing tumorigenesis

项目摘要

Abstract Myelodysplastic syndromes (MDS) are a group of diverse malignant hematological disorders that originate from hematopoietic stem cells (HSCs). Increased levels of reactive oxygen species (ROS) and DNA damage are commonly detected in hematopoietic cells from MDS patients. An elevated level of ROS, generated from either endogenous or exogenous sources including oncogene activation, leads to loss of quiescence and self-renewal of HSCs. ROS-induced DNA damage speeds up the aging process of stem cells and contributes to the mutagenesis associated with cancer development. m6A RNA methylation plays a significant role in multiple biological processes by introducing another layer of post-transcriptional regulation of gene expression within cells. The goal of this project is to elucidate the significant role of ALKBH5-mediated epigenetic regulation in the maintenance of genomic stability in hematopoietic stem/progenitor cell (HSPCs) during oxidative stress, and how deregulation of ALKBH5 contributes to promotion of leukemic transformation of HSPCs in the initiation and development of MDS. We found that ROS significantly increased global m6A RNA methylation in human cell lines, and that the elevation of m6A mRNA methylation is required for rapidly repairing ROS-induced DNA lesions and preventing cell death. Interestingly, we found that ALKBH5, the m6A RNA demethylase, is responsible for ROS-induced elevation of m6A mRNA methylation. ROS induced post- translational modification of ALKBH5, and inhibited the demethylase activity of ALKBH5. We showed that forced expression of ALKBH5 inhibited ROS-induced m6A mRNA methylation and significantly delayed repair of ROS-induced DNA damage. Thus, we hypothesize that aberrant expression of ALKBH5 disrupts HSPC functions by negatively influencing genome integrity and survival of HSPCs, thereby contributing to leukemic transformation of HSPCs during the initiation and development of MDS. In this proposal, we will determine 1) the role and underlying mechanism of ALKBH5 in the maintenance of genomic stability in HSPCs in response to oxidative stress; 2) the effects of ALKBH5/Alkbh5 overexpression on the maintenance of mouse and human primary HSPCs during ROS stress in vivo; and 3) whether ALKBH5/Alkbh5 is required for the maintenance of pre-leukemic stem cells (pre-LSCs) in MDS. Our study will provide new insights into novel mechanisms of MDS development and epitranscriptional regulation of gene expression in HSPCs in response to oxidative stress. Additionally, our study will provide the first set of evidence to support a significant role of ALKBH5- mediated m6A mRNA demethylation in the maintenance of normal HSPCs and pre-leukemic stem cell (pre- LSCs).

摘要