Mutual reinforcement between somatic mutations and transcription factors in clonal hematopoiesis

克隆造血中体细胞突变和转录因子之间的相互强化

基本信息

批准号：
10601791
负责人：
Xiaodong Cheng
金额：
$ 44.51万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10601791
关键词：
Affinity Aging Ascorbic Acid Base Excision Repairs Binding Biochemical Bioinformatics Biological Models Biology Bone Marrow Bone Marrow Transplantation CD34 gene CRISPR/Cas technology Cell Separation Cells Clonal Expansion Cytosine DNA DNA Binding DNA Methylation DNA Repair Enzymes DNA Sequence Alteration DNMT3a Deamination Defect Disease Dysmyelopoietic Syndromes Elderly Enzymes Epigenetic Process Etiology Exhibits Family member Frequencies Functional disorder Genetic Transcription Genome Genomics Guanine Hematology Hematopoiesis Hematopoietic stem cells Human Impairment In Vitro Individual Intervention Investigation Knowledge Maintenance Mediating Methods Methylation Mismatch Repair Mus Mutation Mutation Detection Myeloproliferative disease Output Pathogenesis Pathologic Patients Positioning Attribute Psychological reinforcement Publishing Recording of previous events Reporting Research Rodent Model Role Sampling Scheme Shapes Somatic Mutation Systems Biology Testing Therapeutic Thymine DNA Glycosylase Transcriptional Regulation Untranslated RNA aged base editing clinically relevant demethylation epigenetic regulation epigenome editing epigenomic profiling exome sequencing fitness genome editing genome-wide inhibitor innovation insight mouse model mutant novel novel therapeutics pharmacologic programs repair enzyme response targeted treatment tool transcription factor

项目摘要

Project Summary/ Abstract Recent highthroughput exome sequencing has revealed various somatic mutations in individuals with clonal hematopoiesis (CH) and myelodysplastic syndromes (MDS) patients. Among these mutations, C-to-T mutations is among the most common type of single mutations observed in CH and MDS. It remains yet to be explained why C-to-T mutations are preferentially enriched in CH and MDS and how the C-to-T transition alters hematopoietic stem and progenitor cells (HSPCs) fitness and leads to aberrant clonal expansion. By combining in vitro biochemical and structural analyses with epigenomic profiling of bone marrow samples from MDS patients, the team discovered a previously-underappreciated mutual reinforcement between C-to-T transition and genomic binding of transcription factors (TFs), which contributes to the clonal expansion of HSPCs and aggravate CH and MDS. In Aim1, the team will use genetically-modified mouse models and CRISPR/Cas9- based genome editing methods to probe the causality between C-to-T transition and TF binding in HSPCs. In Aim 2, the team will test how the C-to-T transition and DNA methylation deregulation reshape the genomic distribution of TFs, subsequently altering downstream transcriptional outputs to cause clonal expansion in HSPCs. In parallel, the team will use HSPCs purified from CH and MDS patients to further validate findings made ex vivo and in rodent models. The proposed studies are anticipated to significantly advance our mechanistic understanding on how TFs shape the genome and how somatic mutations alter transcriptional regulation in HSPCs. From a translational perspective, discoveries made from this study will lead to the identification of therapeutic vulnerabilities for CH and MDS treatment.

项目摘要/摘要最近的高通量外显子组测序揭示了克隆个体的各种体细胞突变造血（CH）和骨髓增生综合征（MDS）患者。在这些突变中，C到T 突变是CH和MD中观察到的最常见的单个突变类型。它尚未解释了为什么C-T-T突变优先富含CH和MD，以及C-T-T转变如何改变造血干细胞和祖细胞（HSPC）适应性，并导致异常的克隆膨胀。通过组合通过MDS的骨髓样品的表观基因组分析进行体外生化和结构分析患者，小组发现C-T-T转型之间以前不受欢迎的相互加固转录因子（TFS）的基因组结合，这有助于HSPC的克隆扩张和加重CH和MD。在AIM1中，团队将使用遗传改性的鼠标模型和CRISPR/CAS9- 基于基因组编辑方法，用于探测HSPC中C到T转变与TF结合之间的因果关系。在 AIM 2，团队将测试C-T-T转型和DNA甲基化放松管制如何重塑基因组 TF的分布，随后改变下游转录输出以引起克隆扩张 HSPC。同时，团队将使用从CH和MDS患者纯化的HSPC来进一步验证发现在体内和啮齿动物模型中制成。预计拟议的研究将显着推动我们的关于TF如何塑造基因组以及体细胞突变如何改变转录的机械理解 HSPC中的调节。从转化的角度来看，这项研究的发现将导致鉴定CH和MDS治疗的治疗脆弱性。