• Welcome to the O'Hagan Laboratory

  • Research

    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.

  • Join our group

    Graduate Students

    We accept graduate students through the following programs:

    Postdoctoral Fellows

    Please contact Dr. Heather O’Hagan

  • Lab Members

    Heather M. O’Hagan, Ph.D.

    Assistant Professor of Medical & Molecular Genetics,

    Medical Sciences Program

    B.S. Biology, College of William & Mary

    Ph.D. Cellular and Molecular Biology, University of Michigan Medical School

     

    Samuel Miller

    Genome, Cell and Developmental Biology Graduate Student

    B.S. Genetics, University of Wisconsin-Madison

    Shruthi Sriramkumar

    Cell, Molecular and Cancer Biology Graduate Student

    B.S. Microbiology, University of Mumbai

    M.S. Microbiology, University of Mumbai

    M.S. Biochemistry & Molecular Biology, Georgetown University

    Riddhi Sood

    Genome, Cell and Developmental Biology Graduate Student

    B.S. Biological Sciences, California State University, East Bay

    Ahmed Ghobashi

    Genome, Cell and Developmental Biology Graduate Student

    B.S. School of Pharmacy, Alexandria University, Egypt

    Sudha Savant, Ph.D.

    Postdoctoral Fellow

    B.S. Life Sciences and Biochemistry, University of Mumbai

    M.S. Biological Sciences, Narsee Monjee Institute of Management Studies

    Ph.D. Molecular Biology and Biochemistry, Indiana University School of Medicine

  • Timothy Matthews

    Undergraduate Researcher

    Abriana Warren

    Undergraduate Researcher

    Lauren Lad

    Laboratory Technician

  • Former lab members

    Ning Ding, Ph.D. (former graduate student) - Postdoctoral fellow at MGH Cancer Center

    Ashley R. Mauiri, Ph.D. (former postdoc) – Integrated Nonclinical Development Solutions, Ann Arbor, MI

    Emily Bonham (former undergraduate researcher) – Genetic counseling graduate student, Indiana University School of Medicine

    Mariel Carozza (former undergraduate researcher)

    Michael Peng (former undergraduate researcher) – Medical student, Indiana University School of Medicine

    Victoria Duffin (former laboratory technician) – Laboratory technician at IUPUI

  • Pulliam N, Tang J, Wang W, Fang F, Sood R, O’Hagan H, Miller KD, Clarke R, Nephew KP. (2019) Poly-ADP-Ribosylation of Estrogen Receptor-Alpha by PARP1 Mediates Antiestrogen Resistance in Human Breast Cancer Cells. Cancers. 11(1): pii: E43.

     

    Ding N, Miller S, Savant SS, O’Hagan HM. (2019) JAK2 regulates mismatch repair protein-mediated epigenetic alterations in response to oxidative damage. Environmental & Molecular Mutagenesis. 60(4):308-319.

     

    Savant SS, Sriramkumar S, O’Hagan HM. (2018) The Role of Inflammation and Inflammatory Mediators in the Development, Progression, Metastasis, and Chemoresistance of Epithelial Ovarian Cancer. Cancers. 10(8). pii: E251.

     

    Maiuri, AR, Li, H, Stein, BD, Tennessen, JM, and O'Hagan, HM. (2018) Inflammation-induced DNA methylation of DNA polymerase gamma alters the metabolic profile of colon tumors. Cancer & Metabolism. 6, 9. eCollection 2018.

     

    Tang J, Pulliam N, Özeş A, Buechlein A, Ding N, Keer H, Rusch D, O'Hagan HM, Stack MS, and Nephew KP. (2018) Epigenetic Targeting of Adipocytes Inhibits High-Grade Serous Ovarian Cancer Cell Migration and Invasion. Mol Cancer Res. 16(8):1226-1240.

     

    Vaz M, Hwang SY, Kagiampakis I, Phallen J, Patil A, O'Hagan HM, Murphy L, Zahnow CA, Gabrielson E, Velculescu VE, Easwaran HP, and Baylin SB. (2017) Chronic Cigarette Smoke-Induced Epigenomic Changes Precede Sensitization of Bronchial Epithelial Cells to Single-Step Transformation by KRAS Mutations. Cancer Cell. 32(3):360-376.e6.

     

    Maiuri AR, Peng M, Sriramkumar S, Kamplain CM, DeStefano Shields CE, Sears CL, and O'Hagan HM. (2017) Mismatch Repair Proteins Initiate Epigenetic Alterations during Inflammation-Driven Tumorigenesis. Cancer Res. 77(13):3467-3478. Epub 2017 May 18.

     

    Destefano Shields C, Van Meerbeke SW, Housseau F, Wang H, Huso DL, Casero RA, O'Hagan HM, and Sears, CL. (2016) Reduction of infection-driven tumorigenesis by clearance of enterotoxigenic Bacteroides fragilis in mice. The Journal of Infectious Diseases. 214(1): 122-9.

     

    Ding N, Bonham EM, Hannon BE, Amick TR, Baylin SB and O'Hagan HM. (2016). Mismatch repair proteins recruit DNA methyltransferase 1 to sites of oxidative DNA damage. J Mol Cell Bio. 8(3): 244-54. Epub July 17, 2015.

     

    Calmon MF, Jeschke J, Zhang W, Dhir M, Siebenkas C, Herrera A, Tsai HC, O'Hagan HM, Pappou EP, Hooker CM, Fu T, Schuebel KE, Gabrielson E, Rahal P, Herman JG, Baylin SB and Ahuja N. (2015). Epigenetic silencing of neurofilament genes promotes an aggressive phenotype in breast cancer. Epigenetics. 10(7): 622-32.

     

    O'Hagan HM. (2014). Chromatin modifications during repair of environmental exposure-induced DNA damage: a potential mechanism for stable epigenetic alterations. Environ Mol Mutagen. 55(3): 278-91.

     

    Jeschke J, O'Hagan HM, Zhang W, Vatapalli R, Calmon MF, Danilova L, Nelkenbrecher C, Van Neste L, Bijsmans IT, Van Engeland M, Gabrielson E, Schuebel KE, Winterpacht A, Baylin SB, Herman JG and Ahuja N. (2013). Frequent inactivation of cysteine dioxygenase type 1 contributes to survival of breast cancer cells and resistance to anthracyclines. Clin Cancer Res. 19(12): 3201-11.

     

    O'Hagan HM, Wang W, Sen S, Destefano Shields C, Lee SS, Zhang YW, Clements EG, Cai Y, Van Neste L, Easwaran H, Casero RA, Sears CL and Baylin SB. (2011). Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG islands. Cancer Cell. 20(5): 606-19. PMCID: PMC3220885.

     

    Mohammad HP, Cai Y, McGarvey KM, Easwaran H, Van Neste L, Ohm JE, O'Hagan HM and Baylin SB. (2009). Polycomb CBX7 promotes initiation of heritable repression of genes frequently silenced with cancer-specific DNA hypermethylation. Cancer Res. 69(15): 6322-30.

     

    O'Hagan HM, Mohammad HP and Baylin SB. (2008). Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island. PLoS Genet. 4(8): e1000155. PMCID: PMC2491723.

  • News

    Spring 2019

    Shruthi received the Doane and Eunice Dahl Wright Fellowship to support her graduate research.

    Sam, Shruthi and Riddhi presented their work at the IUSCC Cancer Research Day where Sam and Shruthi received 1st and 2nd place poster presentation awards in the basic sciences.

    Shruthi and Riddhi presented their work at the 21st Annual Midwest DNA Repair Symposium at Washington University in St. Louis where Shruthi won a poster presentation award.

    Sam presented his work at the Cancer Genetics and Epigenetics Gordon Research Conference. Sam received travel awards from the IU Graduate and Professional Government and the IU College of Arts and Sciences to attend this conference.

    Shruthi presented her work at the AACR Annual Meeting.

    Fall 2018

    Sam received the 2018 CTSI Kroenke Poster Award for his poster presentation at the 2018 Indiana CTSI Annual Meeting.

    Shruthi received a IUB Graduate & Professional Student Government Fall Travel Award.

    Sudha received an IUSM Postdoctoral Travel Award to attend the AACR Intestinal Stem Cells and Colon Cancer: Biology to Therapy meeting.

    August 2018

    Dr. Ning Ding successfully defended his thesis and obtained his PhD.

    May 2018

    Ning, Riddhi, Sam, Shruthi, and Sudha presented their work at IU Simon Cancer Center’s Cancer Research Day.

    Ning received a 2nd place poster presentation award in Translational / Clinical Research at Cancer Research Day.

    Shruthi received a 3rd place poster presentation award in Basic Science at Cancer Research Day.

    August 2017

    Ning Ding received the Doane and Eunice Dahl Wright Fellowship to support his graduate research.

    June 2017

    Samuel Miller received an Indiana CTSI Translational Sciences Predoctoral Training Award to support his graduate research.

    May 2017

    Shruthi Sriramkumar and Ning Ding presented their work at the 19th Annual Midwest DNA Repair Symposium at Wright State University.

    Ning Ding won a second place award for his platform presentation at the 19th Annual Midwest DNA Repair Symposium.

  • Connect With Us

    Heather’s email is hmohagan@indiana.edu

    Heather’s office phone: 812-855-3035

    O’Hagan lab phone: 812-855-9068

    We are located in Jordan Hall, Indiana University, Bloomington, Indiana University

  • Funding

    National Institute of Environmental Health Sciences R01

    Collaboration in Translational Research award

    Pre Doctoral Fellowship In Translational Research (to Samuel Miller)

    Pilot Funding for Research Use of Core Facilities

    Collaborative Research Development Grant

    Doane and Eunice Dahl Wright Fellowship (to Shruthi Sriramkumar)