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Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
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Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors

Published on: August 5, 2022

DNMT3B7, a truncated DNMT3B isoform expressed in human tumors, disrupts embryonic development and accelerates

Mrinal Y Shah1, Aparna Vasanthakumar, Natalie Y Barnes

  • 1Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois 60637-1470, USA.

Cancer Research
|July 1, 2010
PubMed

Insights

Truncated DNA methyltransferase 3B (DNMT3B) isoforms contribute to abnormal DNA methylation in cancer. Modeling this in mice reveals how these changes promote lymphoma development and chromosomal instability.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Genetics

Background:

  • Epigenetic alterations, particularly aberrant DNA methylation, are hallmarks of cancer.
  • The precise mechanisms by which cancer cells establish and maintain abnormal DNA methylation patterns remain unclear.
  • Cancer cells often express truncated DNA methyltransferase 3B (DNMT3B) transcripts encoding proteins lacking catalytic activity.

Purpose of the Study:

  • To investigate the in vivo role of a cancer-associated truncated DNMT3B isoform (DNMT3B7) in DNA methylation disruption and cancer development.
  • To model cancer-associated epigenetic changes using transgenic mice.

Main Methods:

  • Generation of transgenic mice expressing the DNMT3B7 isoform.
  • Phenotypic analysis of DNMT3B7 transgenic mice, including embryonic development and cancer incidence.
  • Breeding DNMT3B7 transgenic mice with Emicro-Myc transgenic mice (modeling B-cell lymphoma).
  • Comparative analysis of lymphoma characteristics, including chromosomal rearrangements and DNA methylation patterns.

Main Results:

  • DNMT3B7 transgenic mice displayed developmental abnormalities but rarely developed cancer spontaneously.
  • Co-expression of DNMT3B7 with Emicro-Myc oncogene significantly increased the frequency of mediastinal lymphomas.
  • Lymphomas from Emicro-Myc/DNMT3B7 mice exhibited increased chromosomal rearrangements and global DNA methylation levels.
  • Locus-specific DNA methylation patterns were perturbed in Emicro-Myc/DNMT3B7 lymphomas compared to Emicro-Myc lymphomas.

Conclusions:

  • Truncated DNMT3B isoforms can disrupt DNA methylation patterns in vivo.
  • DNMT3B7 contributes to lymphomagenesis in a relevant cancer model.
  • These findings provide the first in vivo evidence that truncated DNMT3B isoforms promote cancer-associated DNA methylation redistribution.

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