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Altered inflammatory response associated with acquired DNMT3A mutations

与获得性 DNMT3A 突变相关的炎症反应改变

基本信息

批准号：
10394368
负责人：
Minji Byun
金额：
$ 74.88万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10394368
关键词：
Address Affect Age Animal Model Binding Biological Assay Blood Cells Cardiovascular Diseases Cell Differentiation process Cell Lineage Cell model Cells Chromatin Chromatin Remodeling Factor Clonal Expansion Computerized Medical Record Coronary heart disease Coupled DNA DNA Methylation DNMT3a DNMT3a mutation Data Defect Development Diagnosis Disease Disease model Elderly Enrollment Enzymes Epigenetic Process Functional disorder Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Genotype Goals Hematologic Neoplasms Hematopoiesis Hematopoietic Hematopoietic stem cells Human IL6 gene Immunology Individual Inflammation Inflammatory Inflammatory Response Interleukin-6 Knowledge Link Malignant Neoplasms Mediating Modeling Molecular Molecular Profiling Mus Mutate Mutation Mutation Analysis Myeloid Cells Myelopoiesis Nucleic Acid Regulatory Sequences Orthologous Gene Output Pathologic Patients Phenotype Population Heterogeneity Positioning Attribute Predisposition Prevention approach Proteins Proteomics Public Health Regulator Genes Repressor Proteins Research Personnel Risk Role Source Study models System Techniques Technology Time United States aged aging population base biobank cell type chromatin remodeling cohort cytokine design drug use screening epigenetic drug ethnic diversity genetic manipulation genome editing genome-wide genomic locus human embryonic stem cell human pluripotent stem cell induced pluripotent stem cell insight macrophage monocyte mutation carrier neutrophil novel novel strategies novel therapeutic intervention null mutation prevent promoter recruit response single-cell RNA sequencing stem cell biology stem cell model transcription factor transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY The human gene DNMT3A encodes one of the three enzymes that carry out DNA methylation in humans. Clonal expansion of blood cells with acquired mutations in DNMT3A is common in older adults, occurring in 5-10 % of healthy individuals aged 60 or above. Carriers of DNMT3A mutations have an approximately tenfold increased risk of developing hematologic cancers and are twice as likely to develop coronary heart disease. Given the rapidly aging population in the United States and worldwide, understanding the mechanistic basis of the association between acquired DNMT3A mutations in blood cells and increased susceptibility to cancer and cardiovascular disease is tremendously important for public health. Recent studies found evidence of increased inflammation mediated by myeloid cells when the ortholog of DNMT3A was perturbed in animal models. However, the molecular mechanisms underlying this phenomenon and whether DNMT3A mutations affect the inflammatory response of human myeloid cells remain poorly understood. To address this gap in knowledge, we established an experimental system based on myeloid cells differentiated from human pluripotent stem cells. Using this system, we found that human macrophages with DNMT3A mutations displayed altered inflammatory response compared to wild-type macrophages, characterized by augmented expression of IL-6, a potent proinflammatory cytokine. The IL6 promoter was one of the most significantly hypomethylated loci in DNMT3A-mutated macrophages, suggesting a direct mechanistic link between DNA methylation and inflammatory response in our model. In this application, we propose to characterize the molecular signature of the inflammatory response associated with DNMT3A mutations using genetically defined human macrophages and neutrophils and to dissect the epigenetic mechanisms underlying DNMT3A-mediated gene expression regulation. In addition, we will examine the impact of harboring clonally expanded blood cells with DNMT3A mutations on the inflammatory response of primary myeloid cells using a novel single-cell transcriptomic technique. We are in an ideal position to pursue this project given the availability of human pluripotent stem cell-based human myeloid cell models that we have developed and validated, our access to a large biobank representing extremely diverse populations, and the assembly of a strong scientific team consisting of investigators with complementary expertise. Findings from the proposed study will provide critical new insights into the consequence of acquiring DNMT3A mutations on inflammation, and help us develop novel strategies to prevent and treat pathologic conditions related to DNMT3A mutations.

项目总结