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

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

项目成果

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Karim Jean Armache其他文献

Karim Jean Armache的其他文献

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{{ truncateString('Karim Jean Armache', 18)}}的其他基金

Epigenetic mechanisms of regulation of histone lysine methyltransferases involved in leukemia
白血病中组蛋白赖氨酸甲基转移酶调控的表观遗传机制
  • 批准号:
    10736549
  • 财政年份:
    2023
  • 资助金额:
    $ 54.98万
  • 项目类别:
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
  • 批准号:
    10565916
  • 财政年份:
    2022
  • 资助金额:
    $ 54.98万
  • 项目类别:
Structural and functional analysis of gene silencing
基因沉默的结构和功能分析
  • 批准号:
    10459600
  • 财政年份:
    2015
  • 资助金额:
    $ 54.98万
  • 项目类别:
Structural and functional analysis of gene silencing
基因沉默的结构和功能分析
  • 批准号:
    10256729
  • 财政年份:
    2015
  • 资助金额:
    $ 54.98万
  • 项目类别:
Structural and functional analysis of gene silencing
基因沉默的结构和功能分析
  • 批准号:
    10387566
  • 财政年份:
    2015
  • 资助金额:
    $ 54.98万
  • 项目类别:
Structural and functional analysis of gene silencing
基因沉默的结构和功能分析
  • 批准号:
    9272105
  • 财政年份:
    2015
  • 资助金额:
    $ 54.98万
  • 项目类别:
Structural and functional analysis of gene silencing
基因沉默的结构和功能分析
  • 批准号:
    10674754
  • 财政年份:
    2015
  • 资助金额:
    $ 54.98万
  • 项目类别:
STRUCTURAL STUDIES OF EPIGENETIC REGULATORS
表观遗传调控因子的结构研究
  • 批准号:
    8363362
  • 财政年份:
    2011
  • 资助金额:
    $ 54.98万
  • 项目类别:

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