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The role of DNMT3A in gene regulation and stem cell expansion

DNMT3A 在基因调控和干细胞扩增中的作用

基本信息

批准号：
10329918
负责人：
Yung-Hsin Huang
金额：
$ 9.66万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10329918
关键词：
1 year old 3-Dimensional Aberrant DNA Methylation Affect Basic Science Birds Body Regions Body Weight Body fat Bone Marrow CRISPR/Cas technology Cell Count DNA DNA Methylation DNA Modification Methylases DNA methylation profiling DNMT3a DNMT3a mutation Development Disease Doxycycline Education Educational workshop Epigenetic Process FLT3 gene Future Gene Expression Gene Expression Regulation Genes Genome Genomics Goals Hematologic Neoplasms Hematological Disease Hematopoietic stem cells Homeobox Genes Hypermethylation Impairment Investigation Knowledge Lead Length Light Malignant Neoplasms Modification Molecular Mus Mutant Strains Mice Mutate Mutation Pathologic Patients Play Publications Regulation Research Research Personnel Resolution Role Sampling Schools Shapes Stem Cell Development Structure System The Sun Tissues Training Programs Tumor Suppressor Genes Work anticancer research career career development cell type epigenome editing genome-wide genome-wide analysis hematopoietic stem cell differentiation histone modification leukemia leukemic transformation leukemogenesis methylome mouse model mutant mutant mouse model new therapeutic target next generation sequencing novel programs promoter recruit stem cell expansion stem cells three dimensional structure tool transcriptome tumor tumorigenesis

项目摘要

PROJECT SUMMARY DNA methylation is an epigenetic modification that plays a key role in regulating stem cells, development and many diseases. Abnormal DNA methylation has been observed in cancer for more than two decades, with many investigations focusing on promoter hypermethylation, which silences tumor suppressor genes. Additionally, DNMT3A, one of de novo DNA methyltransferases, is frequently mutated in a spectrum of hematological malignancies. Our lab has demonstrated that Dnmt3a loss impairs hematopoietic stem cell (HSC) differentiation, while expanding HSC numbers in bone marrow, suggesting DNMT3A may have a role in tumorigenesis and stem cell regulation. However, DNA methylation profiling of leukemia patient samples shows DNA methylation correlates poorly with gene expression across the genome, highlighting our limited understanding of the specific functions of DNA methylation. Recent studies using a murine model of the most frequent DNMT3A mutation in hematological malignancies, DNMT3AR882, demonstrated that DNMT3AR882 cooperates with FLT3-ITD and NPM1c mutations to contribute to leukemic transformation. Nevertheless, our knowledge of which remaining DNMT3A mutations lead to leukemogenesis and the mechanisms by which they contribute to cancer formation remains lacking. Therefore, the long-term goal of the proposed research is to understand how DNMT3A affects gene regulation in cancer, and how DNMT3A mutants predispose stem cell expansion. In Aim 1, I established a novel DNA epigenome editing tool (dCas9-SunTag-DNMT3A system) to investigate the causal relationship between DNA methylation and gene expression. Using pan-cancer analysis of genome-wide profiles, we have identified DNA hypermethylation occurring in the gene-body regions of canyons (broad and undermethylated regions) with activation of corresponding gene expression. In Aim 2, using a Dnmt3a mutant murine model I developed, I will elucidate the role of one Dnmt3a mutant in priming stem cell expansion. The findings from this proposed research will shed the light on abnormal DNA methylation in cancer and molecular mechanisms of DNMT3A-associated malignancies. Little is known about how mutations in epigenetic modifiers affect the 3D genomic structure in cancer. Therefore, in Aim 3, I plan to use my postdoctoral studies to understand how epigenetic modifiers shape the genomic landscape in cancer and their underlying mechanism. This training program is tailored to give me a comprehensive education in basic science research that will be extremely useful in achieving my long-term career goal of becoming an independent cancer researcher.

项目总结