- Professor, Department of Medicine - Section of Hematology/Oncology, Cancer Research Center, Committee on Cancer Biology
M.D., Northwestern University School
Ph.D., University of California, San Francisco
The University of Chicago
900 East 57th Street
Chicago, Illinois 60637
Phone: (773) 702-4140
Webpage (Cancer Center)
Webpage (Medical Center)
The Role of DNMT3B in Mediating the Abnormal Methylation Patterns of Cancer Cells; Defining the Molecular Events that Accompany Unusual Cases of Hematopoietic Malignancies
Epigenetic changes alter chromatin structure, thereby regulating gene transcription. In normal cells, repetitive DNA is hypermethylated and transcriptionally silent, whereas transcribed gene promoters are undermethylated and associated with open chromatin. Cancer cells are characterized by abnormal DNA methylation. Repetitive DNA sequences and some gene promoters are hypomethylated and transcriptionally active, whereas many tumor suppressor gene promoters are hypermethylated and transcriptionally inactive. Work in my laboratory focuses on elucidating mechanisms that control DNA methylation within cancer cells.
Our laboratory has shown that cancer cells exhibit aberrant splicing of the DNMT3B gene, which encodes one of the three DNA methyltransferases. The aberrant splicing produces DNMT3B transcripts containing premature stop codons, which encode truncated proteins lacking the catalytic domain. We hypothesize that truncated DNMT3B proteins contribute to the abnormal DNA methylation observed in cancer cells, and we are currently testing this hypothesis through a variety of approaches, including using transgenic mice and retroviral infection strategies.
We have developed two lines of transgenic mice that express DNMT3B7, the truncated DNMT3B protein most frequently observed in cancer cells, and these mice exhibit a remarkable phenotype of disrupted embryonic development. These DNMT3B7 transgenic animals provide a model by which we can study the molecular mechanism for the DNA methylation alterations seen in cancer cells. We have crossed them to the Emu-Myctransgenic mice, which are predisposed to the development of B cell lymphomas. Emu-Myc/DNMT3B7 double transgenic mice develop mediastinal tumors much more frequently and within a narrow time frame compared toEmu-Myc single transgenic mice, indicating that DNMT3B7 can alter tumorigenesis. The mediastinal tumors that develop in the double transgenic animals have more chromosomal abnormalities than single transgenic tumors. DNA methylation analyses show that DNA methylation patterns and consequent gene expression are altered in the double transgenic tumors. The Emu-Myc transgenic system shows a crucial dependence on DNA methylation. We are also testing the hypothesis that truncated DNMT3B isoforms regulate DNA methylation within human cancers, with a particular focus on neuroblastoma in conjunction with Dr. Susan Cohn and her laboratory.
In addition to the presence of 5-methylcytosine, we now recognize the existence of 5-hydroxymethylcytosine and other covalent cytosine modifications in mammalian DNA, the function of which is currently under intensive study. In collaboration with the He Laboratory (Department of Chemistry), we have developed a chemical labeling method to detect 5-hydroxymethylcytosine specifically. We are in the process of studying how 5-hydroxymethylcytosine regulates normal hematopoiesis (in collaboration with Dr. Amittha Wickrema) and identifying sites of 5-hydroxymethylcytosine in murine and human tumor samples, with a focus on myeloid malignancies, with the goal of defining the functional significance of this epigenetic alteration.