Heather M. O'Hagan, PhD

Associate Professor of Medical & Molecular Genetics

Email: hmohagan@indiana.edu
Phone: 812-855-3035
Address: Biology Building Room 108
1001 E. 3rd St.
Bloomington, IN 47405
PubMed:

Bio

Dr. Heather M. O’Hagan earned a B.S. in Biology from the College of William and Mary and a Ph.D. in Cellular and Molecular Biology from the University of Michigan. Her doctoral research under the mentorship of Dr. Mats Ljungman focused on mechanisms of activation of the tumor suppressor p53 after DNA damage and the inhibition of transcription. Dr. O’Hagan completed her postdoctoral training in the laboratory of Dr. Stephen Baylin at the Johns Hopkins University where she researched DNA damage-induced epigenetic alterations and how the epigenetic silencing of key genes contributes to carcinogenesis. In 2013, Dr. O’Hagan joined the Indiana University School of Medicine as an Assistant Professor in the Department of Medical and Molecular Genetics and the Medical Sciences Program. In 2021, she was promoted to Associate Professor and gained tenure in 2022. The long-term goal of her group is to understand how epigenetic factors contribute to cancer initiation and progression.

For more information on the research being done in the O'Hagan laboratory please go to http://ohaganlab-iu.strikingly.com/.

Key Publications

Ghobashi AH, Vuong TT, Kimani JW, Ladaika CA, Hollenhorst PC, O’Hagan HM. (2023) Activation of AKT induces EZH2-mediated b-catenin trimethylation in colorectal cancer. iScience. 26(9):107630.

Sriramkumar S, Sood R, Huntington TD, Ghobashi AH, Vuong TT, Metcalfe TX, Wang W, Nephew KP, O'Hagan HM. (2022) Platinum-induced mitochondrial OXPHOS contributes to cancer stem cell enrichment in ovarian cancer. J Transl Med. 20(1):246.

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

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. (2020) LSD1 mediates AKT activity in PIK3CA mutant colorectal cancer. Molecular Cancer Research. 18(2):264-277. Featured as the February 2020 “Editor’s Pick” and cover article.

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

Maiuri AR, Peng M, Sriramkumar S, Kamplain CM, DeStefano Shields CE, Sears CL, O'Hagan HM. (2017) Mismatch Repair Proteins Initiate Epigenetic Alterations during Inflammation-Driven Tumorigenesis. Cancer Res. 77(13):3467-3478. Selected as a NIEHS Extramural Paper of the Month.

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.

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.

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.

Default table
Year	Degree	Institution
2011	Postdoctoral Training	Johns Hopkins University
2004	PhD	University of Michigan
1998	BS	College of William & Mary

The overall focus of the O’Hagan lab is to determine how epigenetic factors contribute to cancer initiation, progression, and therapy response. Previously, we focused on how the acute chromatin response to inflammation and/or DNA damage resulted in heritable epigenetic changes during carcinogenesis. Currently, we are interested in how standard of care therapies and activated signaling pathways lead to altered epigenetic states that promote cancer progression and therapy resistance. We approach our overall research theme from several different directions:

1) Elucidating the role of epigenetic factors in secretory cell specification in colorectal cancer.

BRAF activating mutations occur in approximately 10% of metastatic colorectal cancer (CRCs) and are associated with worse prognosis due to an inferior response to standard chemotherapy. With the use of more potent targeted therapy, shifts in cell identity due to epithelial cell plasticity is an emerging cause of therapy resistance. We have demonstrated that BRAF mutant CRC uniquely contains enteroendocrine cell progenitors that promote cancer cell survival via secreted factors and that the differentiation state of these tumors is regulated by the lysine demethylase LSD1. We are currently exploring the role of enteroendocrine cells in promoting therapy resistance in BRAF mutant CRC and the mechanisms by which epigenetic factors regulate secretory cell differentiation in these cancers. We are also studying how secretory cells present in CRC interact with and alter the tumor immune microenvironment.

2) The role of altered DNA methylation 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.

3) The mechanism by which signaling pathway activation alters the function of chromatin remodelers.

Oncogenic mutations often result in aberrant activation of signaling pathways in cancer cells. Signaling pathways can alter the function of chromatin remodelers, which can in turn modify expression of genes that affect signaling pathways. We are exploring the connections between signaling pathway activation, function of chromatin remodelers, transcriptional responses, and cancer cell plasticity.

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Heather M. O'Hagan, PhD

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