Member Biography

Heather M. O'Hagan, Ph.D.
Heather O'Hagan

Heather O'Hagan, Ph.D.

1001 E. 3rd Street
Jordan Hall, Room 108
Bloomington, IN 47405
Phone: (812) 855-3035

Research Program Membership

Full member:

Assistant Professor of Medical and Molecular Genetics
Department of Medical and Molecular Genetics
IU School of Medicine

Adjunct Assistant Professor of Bioogy
Indiana University, Bloomington, Indiana

Dr. O'Hagan's research interests include:

The overall focus of the O’Hagan lab is to understand how the acute chromatin response to inflammation and/or DNA damage results in heritable epigenetic changes during carcinogenesis. Inflammation contributes to the development of a diverse array of diseases, including colorectal cancer (CRC). At sites of chronic inflammation epithelial cells are exposed to high levels of reactive oxygen species and undergo cancer-associated DNA methylation changes, suggesting that inflammation initiates epigenetic alterations. Cancer cells are globally DNA hypomethylated but have aberrant gains in promoter DNA methylation that transcriptionally silence tumor suppressor genes, linking DNA methylation directly to tumorigenesis. However, the mechanisms of targeting and initiation for these stable disease-specific epigenetic marks are not completely understood. We approach our overall research theme from several different directions: 1) The mismatch repair protein dependent epigenetic response to oxidative damage. We have linked inflammation and oxidative DNA damage to acute changes in the interaction of epigenetic silencing proteins with each other and the chromatin. The mismatch repair (MMR) protein heterodimer MSH2-MSH6 participates in the oxidative damage-induced recruitment of DNA methyltransferase 1 (DNMT1) to chromatin where it reduces transcription at sites of oxidative damage. The response of MSH2-MSH6 to oxidative damage is dependent on non-canonical activation of JAK2. To connect these findings to epigenetic changes in tumors we used an in vivo model of inflammation-driven colon tumorigenesis. Using genome-wide DNA methylation techniques we demonstrated that the epigenetic response to oxidative damage results in the DNA hypermethylation and silencing of tumor suppressor genes. Altogether, this work suggests a novel mechanism by which oxidative damage induces acute epigenetic changes through the interaction of DNMT1 with MMR proteins and that these acute changes drive DNA methylation alterations during tumorigenesis. Current work focuses on using dietary compounds and chemical inhibitors to reverse inflammation-induced epigenetic changes and reduce tumorigenesis. 2) Inflammation-induced epigenetic alterations create and maintain an altered cellular state that has transformative properties. Colonoids derived from stem cells or crypts isolated from mouse or human colons form budding structures. They lack other cell types and therefore provide an effective approach to study effects of genetic and epigenetic changes in stem and epithelial cells. We are currently using colonoids to understand how inflammation-induced epigenetic alterations prime cells for oncogenic transformation. 3) The mechanism by which chromatin remodelers alter transcription in response to oxidative stress. Oxidative stress activates many downstream signaling pathways. Signaling pathways can alter the function of epigenetic modifiers, which can in turn modify expression of genes that affect signaling pathways. Mutations can also result in aberrant activation of these signaling pathways in cancer cells. We are exploring the connection between activation of signaling pathways, function of epigenetic modifiers, and transcriptional responses. 4) The role of DNA repair proteins and altered DNA damage responses in establishing and maintaining platinum resistance in ovarian cancer. Development of chemoresistance is one of the primary causes for high mortality rates in ovarian cancer. Several groups have established that epigenetic mechanisms like aberrant promoter DNA methylation of tumor suppressor genes, DNA repair genes, pro-apoptotic genes and their subsequent transcriptional repression contribute to the development of platinum resistance. We are investigating how aberrant DNA methylation and subsequent transcriptional repression is initiated during acquisition of platinum resistance. Ovarian cancer stem cells are also enriched in recurrent platinum resistant tumors. Additional work in our group examines how the DNA damage response is altered in ovarian cancer stem cells to allow them to survive platinum treatment.

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Post-doctoral Fellowship - The Johns Hopkins Unversity School of Medicine, Baltimore, MD 2010

Ph.D. - University of Michigan, Ann Arbor, MI 2004