864-889-0519 chg@clemson.edu

Dr. Tara Doucet-O’Hare

Tara Doucet OHare

Tara Doucet OHare

Assistant Professor, Department of Genetics and Biochemistry

Biosketch

I received my Bachelor of Arts in Biological Sciences with a minor in Spanish from Clemson University in South Carolina in 2010. I then attended the Johns Hopkins School of Medicine (Baltimore, MD) and earned a Ph.D. in Human Genetics, and graduated in 2016. I began my first post-doctoral research position at the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health (NIH) in the lab of Avindra Nath M.D. in 2016 (Bethesda, MD). In 2021, I started as a Research Fellow at the National Cancer Institute (NCI) in the lab of Dr. Zhengping Zhuang. I joined Clemson University as an assistant professor in August of 2024 in the Department of Genetics and Biochemistry (Clemson, SC).

Research

In graduate school, I was introduced to transposable elements and their role in genome evolution and plasticity, normal development, and disease. Transposable elements (TEs) are mobile DNA sequences that can replicate themselves through a ‘copy and paste’ or a ‘cut and paste’ mechanism in the genomic DNA of their host. Although historically referred to as ‘selfish’ and ‘junk’ DNA, TEs comprise nearly half of the human genome, and some play a critical role in normal human development. I studied the transposable element Long Interspersed Nuclear Element 1 (LINE1) and its active ‘jumping’ or retrotransposition in normal somatic cells and esophageal and colorectal tumors. My work studying the active retrotransposition of LINE1 in both normal esophagus and squamous cell carcinoma demonstrated that TEs can be active in specific permissive normal tissues, and these cells often clonally expand in the resulting tumor.

My interest in transposable elements spurred me to continue to work in the field of TEs during my post-doctoral work, where I studied the expression of the Human Endogenous Retrovirus K (HERV-K, subtype HML-2) in neurodevelopment and neurodifferentiation. Endogenous retroviruses comprise 8% of the human genome and originate from exogenous retroviruses whose genomes were incorporated into the germline and are inherited in a Mendelian fashion. Endogenous retroviral genes have been co-opted for both physiologic and pathologic purposes, both in cancer where their envelope (env) proteins can contribute to immunosuppression, facilitate cell proliferation, and contribute to the formation of multinucleated syncytia and in neurodegeneration where env proteins lead to cytotoxicity in cortical neurons. Endogenous retrovirus expression is normally tightly spatially and temporally regulated but downregulated as cells differentiate and mature.

Genetic mutations in SWI/SNF (SWItch/Sucrose Non-Fermentable) proteins, which regulate chromatin remodeling during development, occur in 25% of tumors. Tumors that harbor SWI/SNF loss of function mutations are frequently malignant undifferentiated cancers with no targeted treatments and high morbidity and mortality.1 In my previous studies, I have shown that the loss of function of SMARCB1, a core protein in the SWI/SNF complex, leads to persistent expression post-development of endogenous retroviruses (ERV) in the pediatric central nervous system tumor Atypical Teratoid Rhabdoid Tumor (AT/RT). Alterations in chromatin remodeling by the SWI/SNF proteins have also been observed in tissues from individuals with Amyotrophic Lateral Sclerosis (ALS), a heterogeneous motor neuron disease that occurs sporadically and, in nearly all cases, has no known genetic etiology and no targeted treatments.

Significant changes in chromatin structure can lead to transcriptional activation of genes, which are normally silenced post-differentiation and post-development, such as Human Endogenous Retrovirus K (HERV-K, subtype HML-2). I hypothesize that the timing of the loss of functional SWI/SNF proteins during early neurodevelopment or following terminal differentiation in the central nervous system can lead to aberrant expression of endogenous retroviruses followed by tumor formation or neurodegeneration. I am currently exploring these processes using both in vitro techniques with cell lines and in vivo techniques using the chicken embryo model. My research has the potential to further elucidate similar fundamental mechanisms, which will provide valuable biological insights and potentially lead to the development of novel therapeutics for multiple diseases with a commonality of ERV involvement in pathogenesis and no targeted therapy available.

PUBLISHED MANUSCRIPTS

  1. Shah AH, Rivas SR, Doucet-O’Hare TT, Govindarajan V, DeMarino C, Wang T, Ampie L, Zhang Y, Banasavadi-Siddegowda YK, Walbridge S, Maric D, Garcia-Montojo M, Suter RK, Lee MH, Zaghloul KA, Steiner J, Elkahloun AG, Chandar J, Seetharam D, Desgraves J, Li W, Johnson K, Ivan ME, Komotar RJ, Gilbert MR, Heiss JD, Nath A. Human endogenous retrovirus K contributes to a stem cell niche in glioblastoma. J Clin Invest. 2023 Jul 3;133(13):e167929. doi: 10.1172/JCI167929. PMID: 37395282; PMCID: PMC10313366.
  2. Steiner JP, Bachani M, Malik N, DeMarino C, Li W, Sampson K, Lee MH, Kowalak J, Bhaskar M, Doucet-O’Hare TT, Garcia-Montojo M, Cowen M, Smith B, Reoma LB, Medina J, Brunel J, Pierquin J, Charvet B, Perron H, Nath A. Human Endogenous Retrovirus K Envelope in Spinal Fluid of Amyotrophic Lateral Sclerosis Is Toxic. Ann Neurol. 2022 Oct;92(4):545-561. doi: 10.1002/ana.26452. Epub 2022 Jul 30. PMID: 35801347; PMCID: PMC9489628.
  3. Shah AH, Govindarajan V, Doucet-O’Hare TT, Rivas S, Ampie L, DeMarino C, Banasavadi-Siddegowda YK, Zhang Y, Johnson KR, Almsned F, Gilbert MR, Heiss JD, Nath A. Differential expression of an endogenous retroviral element [HERV-K(HML-6)] is associated with reduced survival in glioblastoma patients. Sci Rep. 2022 Apr 27;12(1):6902. doi: 10.1038/s41598-022-10914-5. PMID: 35477752; PMCID: PMC9046263.
  4. Shah AH, Suter R, Gudoor P, Doucet-O’Hare TT, Stathias V, Cajigas I, de la Fuente M, Govindarajan V, Morell AA, Eichberg DG, Luther E, Lu VM, Heiss J, Komotar RJ, Ivan ME, Schurer S, Gilbert MR, Ayad NG. A multiparametric pharmacogenomic strategy for drug repositioning predicts therapeutic efficacy for glioblastoma cell lines. Neurooncol Adv. 2021 Dec 31;4(1):vdab192. doi: 10.1093/noajnl/vdab192. PMID: 35118385; PMCID: PMC8807341.
  5. Doucet-O’Hare TT, DiSanza BL, DeMarino C, Atkinson AL, Rosenblum JS, Henderson LJ, Johnson KR, Kowalak J, Garcia-Montojo M, Allen SJ, Orr BA, Santi M, Wang T, Fathi S, Lee MH, Sampson K, Li W, Zhuang Z, Nath A. SMARCB1 deletion in atypical teratoid rhabdoid tumors results in human endogenous retrovirus K (HML-2) expression. Sci Rep. 2021 Jun 18;11(1):12893. doi: 10.1038/s41598-021-92223-x. PMID: 34145313; PMCID: PMC8213802.
  6. Wang T, Medynets M, Johnson KR, Doucet-O’Hare TT, DiSanza B, Li W, Xu Y, Bagnell A, Tyagi R, Sampson K, Malik N, Steiner J, Hadegan A, Kowalak J, O’Malley J, Maric D, Nath A. Regulation of stem cell function and neuronal differentiation by HERV-K via mTOR pathway. Proc Natl Acad Sci U S A. 2020 Jul 28;117(30):17842-17853. doi: 10.1073/pnas.2002427117. Epub 2020 Jul 15. PMID: 32669437; PMCID: PMC7395438.
  7. Doyle GA, Doucet-O’Hare TT, Hammond MJ, Crist RC, Ewing AD, Ferraro TN, Mash DC, Kazazian HH Jr, Berrettini WH. Reading LINEs within the cocaine addicted brain. Brain Behav. 2017 Apr 6;7(5):e00678. doi: 10.1002/brb3.678. PMID: 28523221; PMCID: PMC5434184.
  8. Doucet-O’Hare TT, Sharma R, Rodić N, Anders RA, Burns KH, Kazazian HH Jr. Somatically Acquired LINE-1 Insertions in Normal Esophagus Undergo Clonal Expansion in Esophageal Squamous Cell Carcinoma. Hum Mutat. 2016 Sep;37(9):942-54. doi: 10.1002/humu.23027. Epub 2016 Jul 13. PMID: 27319353; PMCID: PMC5548391
  9. Doucet-O’Hare TT, Rodić N, Sharma R, Darbari I, Abril G, Choi JA, Young Ahn J, Cheng Y, Anders RA, Burns KH, Meltzer SJ, Kazazian HH Jr. LINE-1 expression and retrotransposition in Barrett’s esophagus and esophageal carcinoma. Proc Natl Acad Sci U S A. 2015 Sep 1;112(35):E4894-900. doi: 10.1073/pnas.1502474112. Epub 2015 Aug 17. Erratum in: Proc Natl Acad Sci U S A. 2016 Jan 5;113(1):E104. PMID: 26283398; PMCID: PMC4568228
  10. Ingram-Smith C, Wharton J, Reinholz C, Doucet TT, Hesler R, Smith, K. (2015) “The Role of Active Site Residues in ATP Binding and Catalysis in the Methanosarcina thermophila Acetate Kinase.” Life 5, no. 1: 861-871. PMID: 25775277.
  11. Solyom S, Ewing AD, Rahrmann EP, Doucet TT, Nelson HH, Burns MB, Harris RS, Sigmon DF, Casella A, Erlanger B, Wheelan S, Upton KR, Shukla R, Faulkner GJ, Largaespada DA, Kazazian HH Jr. (2012) Extensive somatic L1 retrotransposition in colorectal tumors. Genome Research. December (12):2328-2338. PMID: 22968929.

REVIEWS/ BOOK CHAPTERS

  1. DeMarino C*, Nath A, Zhuang Z, and Doucet-O’Hare TT*. Does interplay between human endogenous retrovirus and extracellular vesicles contribute to aging? Published online October 27, 2023 at Extracellular Vesicles and Circulating Nucleic Acids.
  2. Dang DD, Rosenblum JS, Shah AH, Zhuang Z, Doucet-O’Hare TT. Epigenetic Regulation in Primary CNS Tumors: An Opportunity to Bridge Old and New WHO Classifications. Cancers (Basel). 2023 Apr 27;15(9):2511. doi: 10.3390/cancers15092511. PMID: 37173979; PMCID: PMC10177493.
  3. Rivas SR, Valdez MJM, Govindarajan V, Seetharam D, Doucet-O’Hare TT, Heiss JD, Shah AH. The Role of HERV-K in Cancer Stemness. Viruses. 2022 Sep 12;14(9):2019. doi: 10.3390/v14092019. PMID: 36146825; PMCID: PMC9504571.
  4. Doucet-O’Hare TT, Rosenblum JS, Shah AH, Gilbert MR, Zhuang Z. Endogenous Retroviral Elements in Human Development and Central Nervous System Embryonal Tumors. J Pers Med. 2021 Dec 8;11(12):1332. doi: 10.3390/jpm11121332. PMID: 34945804; PMCID: PMC8708524.
  5. Wang T, Doucet-O’Hare TT, Henderson L, Abrams RPM, Nath A. Retroviral Elements in Human Evolution and Neural Development. J Exp Neurol. 2021;2(1):1-9. PMID: 33693440; PMCID: PMC7943042.
  6. Garcia-Montojo M, Doucet-O’Hare TT, Henderson L, Nath A. Human endogenous retrovirus-K (HML-2): a comprehensive review. Crit Rev Microbiol. 2018 Nov;44(6):715-738. doi: 10.1080/1040841X.2018.1501345. Epub 2018 Oct 14. PMID: 30318978; PMCID: PMC6342650
  7. Doucet-O’Hare, TT, & Kazazian, H (2017). Retrotransposon contribution to genomic plasticity. In Human Retrotransposons in Health and Disease (pp. 63-93). Springer International Publishing. https://doi.org/10.1007/978-3-319-48344-3_3. Date: 01/07/2017
  8. Doucet, TT and Haig H. Kazazian Jr. (2017) “Long interspersed element sequencing (L1-seq): a method to identify somatic LINE-1 insertions in the human genome. Methods in Molecular Biology. 1400:79-93. PMID: 26895047. Date:03/07/2017

 

Complete List of Published Works in My Bibliography

https://www.ncbi.nlm.nih.gov/myncbi/tara.doucet-o’hare.1/bibliography/public/