Date of Award

Spring 5-7-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Genetics, Cell Biology & Anatomy

First Advisor

Rene Opavsky

Abstract

DNA methylation is an epigenetic modification that regulates gene transcription. The addition of a methyl group to cytosine is catalyzed by a family of enzymes known as DNA methyltransferases (Dnmts). The three catalytically active Dnmts in humans and mice are Dnmt1, Dnmt3a, and Dnmt3b. DNA methylation is clinically relevant, as aberrations in the methylation landscape are a hallmark of nearly all human cancers. Cancer methylomes are typically characterized by genome wide hypomethylation and regional specific hypermethylation, both of which have been linked to alterations in gene expression. In order to understand the contribution of epimutations to the development of hematological malignancies we created several mouse models in which one or more Dnmt is deleted in hematopoietic stem cells and all downstream lineages. This allowed us to address the role of individual Dnmts in normal and malignant hematopoiesis. We found that Dnmts contribute to the cancer methylome through both de novo and maintenance methylation, and that activities of individual Dnmts seldom overlap with one another. We identified Dnmt1 as being critical for T cell development and maintenance of the tumor phenotype in T cell lymphomas. Furthermore, we identified Dnmt3a and Dnmt3b as critical tumor suppressor genes in the prevention of chronic lymphocytic leukemia in mice. Collectively, these studies provide insight into the effects of Dnmt deregulation in tumorigenesis.

ONC1.docx (190 kB)
LEU1.docx (188 kB)
MCB1.docx (134 kB)

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