Frederick Domann, PhD

Professor
Radiation Oncology

Office: B152 ML
Office Phone: 319-335-8018

Lab: B171 ML
319-335-8024


Lab Website: http://frrbp.medicine.uiowa.edu/domann-lab

Epigenetic mechanisms of gene silencing in cancer Metabolic control of chromatin accessibility and gene expression Role of antioxidant enzymes in cancer

My laboratory focuses on how chromatin structure participates in the transcriptional regulation of cancer related genes including oncogenes and tumor suppressor genes. We are studying the molecular mechanisms by which aberrant cytosine methylation of CpG dinucleotides and post-translational modifications on histones affect gene expression during the development and progression of cancer. A gene of particular interest in our laboratory is the tumor suppressor gene SOD2 that encodes the antioxidant enzyme superoxide dismutase. We have determined that DNA methylation as well as transcriptionally repressive histone modifications at an upstream enhancer element on the SOD2 promoter can suppress its transcriptional activation. We are also assessing chromatin accessibility in the region of the SOD2 promoter in cells that differentially express the gene. We are currently using conditional knockout mice to study how the loss of SOD2 leads to various pathological conditions, particularly cancer.

We are also studying AP-2 family transcription factors and their interactions with the SOD2, Erα, and other gene promoters, particularly in breast cancer. Interestingly, AP-2 DNA binding is inhibited by cytosine methylation and it is a redox sensitive factor. Our future research directions will be aimed at elucidating the role of cytosine methylation as a mechanism for inactivation of other genes involved in protection against oxidative damage as well as other classical tumor suppressor genes, and to elucidate the mechanism(s) by which CpG methylation can bring about these changes in gene expression. The recent availability of a conditional knockout mouse for AP-2g will facilitate mechanistic studies of the role for AP-2 g in breast cancer.

We have recently become interested in the extracellular form of SOD encoded by the SOD3 gene. This is a potent modifier of redox tone in the tissue microenvironment and we have discovered that SOD3 is a potent inhibitor of experimental lung metastases by human breast cancer cells at least in part due to its inhibitory effects on heparanase expression.

PubMed link

Department/Program Affiliations:
Free Radical and Radiation Biology
Molecular Medicine
MSTP
Pathology
Radiation Oncology