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Molecular basis for aberrant de novo DNA methylation in cancer

癌症中异常 DNA 从头甲基化的分子基础

基本信息

批准号：
10565916
负责人：
Karim Jean Armache
金额：
$ 52.18万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
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：
2022-02-07 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10565916
关键词：
Ablation Binding Biochemistry Cancer Biology Cell Differentiation process Cells Cellular Assay Chromatin Complex CpG Islands CpG dinucleotide Cryoelectron Microscopy Cytosine DNA DNA Methylation DNA Modification Methylases DNMT3B gene DNMT3a DNMT3a mutation Development Enzymes Epigenetic Process Equilibrium FDA approved Family Foundations Frequencies Gene Expression Regulation Genes Genetic Genomics Histones Human Hypermethylation Impairment Individual Intercistronic Region Length Malignant Neoplasms Mediating Meta-Analysis Methylation Methyltransferase Missense Mutation Modeling Molecular Molecular Conformation Monoubiquitination Mus Mutate Mutation N-terminal Neoplastic Cell Transformation Normal tissue morphology Nucleosomes Oncogenic Organoids PRC1 Protein Patients Pattern Play Polycomb Post-Translational Protein Processing Protein Isoforms Publishing RNA Splicing Recurrence Regulation Role Sampling Site Structure Testing Therapeutic Therapeutic Index Tissue Differentiation Tissues Toxic effect Tumor Suppressor Genes Variant Work cancer cell cancer initiation chromatin modification design epigenomics genome-wide histone modification human disease inhibitor insight interdisciplinary approach member novel promoter recruit stem cells tumor tumorigenesis

项目摘要

PROJECT SUMMARY Methylation of cytosine in the context of CpG dinucleotides is an essential and highly conserved chromatin modification. It plays a critical role in gene regulation, cell differentiation and organismal development. Aberrant patterns of DNA methylation are commonly observed in human diseases including cancer. CpG islands (CGIs), regions with a high frequency of CpG sites found at the promoters of ~40% mammalian genes, are devoid of DNA methylation in normal tissues but become hypermethylated in tumors, leading to the silencing of many tumor suppressor genes. However, the molecular mechanisms underlying CGI hypermethylation in cancer remain poorly understood, and therefore therapeutic strategies that specifically target CGI hypermethylation are lacking. DNA methylation is established by the DNMT3 family of de novo DNA methyltransferases. The DNMT3 family includes two catalytically active members, DNMT3A and DNMT3B. DNMT3A has two splice variants DNMT3A1 and DNMT3A2. While DNMT3A2 and DNMT3B are expressed during early development, DNMT3A1 is the main de novo DNA methyltransferase expressed in differentiated tissues. We and others have previously demonstrated that DNMT3A1 contains regulatory domains interacting with histone post-translational modifications (PTMs) to guide its genomic targeting to regions marked by H3K36 di- and tri-methylation (H3K36me2/3). Our collaborative preliminary studies have identified an additional functional domain unique to DNMT3A1 that facilitates its interaction with histone H2AK119 mono-ubiquitination (H2AK119Ub), a PTM catalyzed by Polycomb Repressive Complex 1 (PRC1). These findings resonate with meta-analyses of patient tumor samples, which revealed a strong correlation between CGIs that gain methylation in cancers and those regulated by Polycomb complexes in normal tissues. We will pursue a hypothesis that the redistribution of DNMT3A1 from H3K36 methylation to H2AK119ub-marked CGIs drives CGI hypermethylation and neoplastic transformation. To test this hypothesis, we will employ a multidisciplinary approach that leverages the complementary expertise of Armache and Lu labs, spanning from chromatin biochemistry, structural study to cancer biology and epigenomics. These studies will reveal the molecular mechanisms of DNMT3A1 regulation by H3K36 methylation and H2AK119Ub and uncover how the balance between these PTMs mediates the recruitment, activity and function of DNMT3A1 in healthy tissues and tumors. Expected results will provide an enhanced understanding of the dynamics, cause and consequence of CGI hypermethylation – a molecular hallmark of human cancers that remains a key focus of the field. Furthermore, they will lay the foundation for developing inhibitors that target the interaction of DNMT3A1 with H2AK119Ub to specifically reverse cancer- associated CGI hypermethylation, which are expected to show less toxicity compared to current FDA-approved unspecific DNA hypomethylating agents.

项目总结