The overall focus of the O’Hagan lab is to determine how epigenetic factors contribute to cancer initiation, progression and therapy response. We study how the acute chromatin response to inflammation and/or DNA damage results in heritable epigenetic changes during carcinogenesis. We are also interested in how altered epigenetic states promote cancer. We approach our overall research theme from several different directions:
1) The mismatch repair protein dependent epigenetic response to oxidative damage.
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. 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. Our 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 hypermethylation are linked 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.
5) Elucidating the role of epigenetic factors in secretory cell specification in colorectal cancer.
Mucinous colorectal cancer (CRC) makes up 10-20% of total CRC and has distinct clinical features and molecular alterations from non-mucinous CRC. We have demonstrated that secretory cell progenitors are enriched in BRAF mutant mucinous CRC relative to the normal colon and non-mucinous CRC. Interestingly, secretory enteroendocrine cells are maintained in a progenitor state by a lysine demethylase 1 (LSD1) and DNA methyltransferase dependent mechanism. We are currently exploring the role of secretory progenitors in promoting mucinous CRC and the mechanisms by which epigenetic factors regulate secretory cell differentiation in mucinous CRC.
Heather M. O’Hagan, Ph.D.
Associate 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
Genome, Cell and Developmental Biology Graduate Student
B.S. School of Pharmacy, Alexandria University, Egypt
Genome, Cell and Developmental Biology Graduate Student
B.S. Molecular Genetics, The Ohio State University
Genome, Cell and Developmental Biology Graduate Student
Cell, Molecular and Cancer Biology Graduate Student
Former lab members
Shruthi Sriramkumar, Ph.D. (former graduate students) - Postdoctoral researcher, Dr. Rugang Zhang's lab at The Wistar Institute
Riddhi Sood, Ph.D. (former graduate student) - Field Application Scientist, Thermo Fisher Scientific
Samuel Miller, Ph.D. (former graduate student) - Computational Biologist, Cellarity
Sudha S. Savant, Ph.D. (former postdoc) - Senior Application Scientist, Beckman Coulter Life Sciences
Ning Ding, Ph.D. (former graduate student) - Scientist, Biogen
Ashley R. Maiuri, Ph.D. (former postdoc) – Toxicology Consultant, Integrated Nonclinical Development Solutions
Emily Bonham (former undergraduate researcher)
Timothy Matthews (former undergraduate researcher)
Abriana Warren (former undergraduate researcher)
Lauren Lad (former undergraduate researcher)
Mariel Carozza (former undergraduate researcher)
Michael Peng (former undergraduate researcher)
Sikai Xiao (former laboratory technician) - Graduate Student Dartmouth College
Victoria Duffin (former laboratory technician) – Laboratory technician at IUPUI
For full list see: https://www.ncbi.nlm.nih.gov/myncbi/heather.o'hagan.1/bibliography/public/
Miller SA, Policastro RA, Sriramkumar S, Lai T, Huntington TD, Ladaika CA, Kim D, Hao C, Zentner GE, O’Hagan HM. (2021) LSD1 and aberrant DNA methylation mediate persistence of enteroendocrine progenitors that support BRAF mutant colorectal cancer. Cancer Research. 81(14):3791-3805.
DeStefano Shields CE, White JR, Chung L, Wenzel A, Hicks JL, Tam AJ, Chan JL, Dejea CM, Fan H, Maiuri AR, Sriramkumar S, Podicheti R, Rusch DB, Wang H, De Marzo AM, Huso DL, Besharati S, Anders RA, Baylin SB, O'Hagan HM#, Housseau F#, Sears CL#. (2021) Bacterial-driven inflammation and mutant BRAF expression combine to promote murine colon tumorigenesis that is sensitive to immune checkpoint therapy. Cancer Discovery. 11(7):1792-1807. #Co-corresponding authors
Miller SA, Ghobashi AH, O’Hagan HM. (2021) Consensus molecular subtyping of colorectal cancers is influenced by goblet cell content. Cancer Genetics. 254-255:34-39.
Sriramkumar S, Matthews TD, Ghobashi AH, Miller SA, VanderVere-Carozza PS, Pawelczak KS, Nephew KP, Turchi JJ, O’Hagan HM. (2020) Platinum-Induced Ubiquitination of Phosphorylated H2AX by RING1A is Mediated by Replication Protein A in Ovarian Cancer. Molecular Cancer Research. 18(11):1699-1710.
Miller SA, Policastro RA, Savant SS, Sriramkumar S, Ding N, Lu X, Mohammad HP, Cao S, Kalin JH, Cole PA, Zentner GE, O’Hagan HM. (2019) LSD1 mediates AKT activity in PIK3CA mutant colorectal cancer. Molecular Cancer Research. 18(2):264-277. Featured as the February 2020 “Editor’s Pick”.
Maiuri AR, Savant SS, Podicheti R, Rusch DB, O'Hagan HM. (2019) DNA methyltransferase inhibition reduces inflammation-induced colon tumorigenesis. Epigenetics. 14(12):1209-1223.
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. Selected as "Editor's Choice Article".
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.
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.
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.
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.
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.
Shruthi successfully defended her PhD thesis!
Ahmed and Chris presented their work at the IUSCCC Cancer Research Day where Ahmed received a 2nd place poster presentation award.
Heather's promotion to Associate Professor was approved by the IU Board of Trustees.
Sam and Riddhi successfully defended their PhD theses!
Ahmed received the Doane and Eunice Dahl Wright Fellowship to support his graduate research.
Shruthi Sriramkumar presented her work at the 2020 Annual EMGS meeting.
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.
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.
Dr. Ning Ding successfully defended his thesis and obtained his PhD.
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.
Ning Ding received the Doane and Eunice Dahl Wright Fellowship to support his graduate research.
Samuel Miller received an Indiana CTSI Translational Sciences Predoctoral Training Award to support his graduate research.
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.
Heather’s email is hmohagan@
Heather’s office phone: 812-855-3035
O’Hagan lab phone: 812-855-9068
We are located in Biology Building, Indiana University, Bloomington, Indiana University
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 Fellowships (to Ning Ding, Shruthi Sriramkumar, Ahmed Ghobashi)
Department of Defense Ovarian Cancer Research Program