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Dean Tantin

Professor of Microbiology and Immunology

Gene Regulation in T cells, in T cell memory and autoimmunity, in Stem Cells and in Cancer

Dean Tantin

 

Molecular Biology Program

Education

B.S. University of California, San Diego

Ph.D. University of California, Los Angeles

 

Research

The major focus of our research is the regulation of gene expression, in particular the control of immune responses and stem cell function by sequence-specific, DNA binding transcription factors. Sequence-specific DNA binding transcription factors are by far the most potent and specific controllers of gene expression. The ability of these factors to coordinate gene expression programs explains why they are the central mediators of development, signal response and cell fate reprogramming. It also explains why aberrations in transcription factor function can lead to developmental defects, immune dysfunction and cancer. Our lab studies mammalian transcription factors, their upstream regulatory signals and downstream cofactors and mechanisms, to answer fundamental questions regarding lymphocyte development and function, stem cells, pluripotency and malignancy. We use mouse genetic models and derived cells, as well as human cells, along with genomic, molecular biological and biochemical approaches.

A unifying theme of the lab is the Oct/POU transcription factor family as well as family member cofactors. One focus of the lab is the establishment and loss of pluripotency during development. Pluripotency refers to the capacity to make all cells and tissues of the embryo. Two cultured cell types with this capability are called embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Two transcription factors of particular interest are Oct4 and its paralog Oct1. Oct4 is expressed in the early embryo. Oct1 is co-expressed with Oct4 but is also maintained after differentiation and loss of pluripotency. One of the most striking features of Oct1 loss is developmental lethality at mid-gestation, with severe anemia. We have found that in the absence of Oct1, mouse ESCs appear normal until differentiated. Differentiating cells towards mesoderm (which makes blood and muscle among other cell types), we find that Oct1 deficiency results in a developmental “wrong turn” in which cells proceed down abnormal differentiation pathways. Using a variety of genomic and biochemical approaches, we have found that Oct1 replaces Oct4 as stem cells differentiate, to help induce developmentally poised mediators. Oct1 and its lymphocyte-restricted cofactor OCA-B/Pou2af1 operate similarly in CD4+ T cells to promote memory responses.

Major projects in the lab include:

  1. Roles of the transcriptional cofactor OCA-B/Pou2af1/Bob.1 in T cell memory, autoimmunity and anti-tumor immunity
  2. Investigating OCA-B as a possible drug target
  3. Oct1/4 interplay in pluripotent cells and their differentiated progeny
  4. Redox regulation of Oct4 and implications in reprogramming and peri-implantation development
  5. Conformation-specific cofactors of DNA-bound Oct4
  6. Role of Oct1 during blood cell differentiation, including in human stem cells
  7. Oct1 as a biomarker of small intestinal adenocarcinoma

 

Image
Comparative single-cell RNA-seq UMAP projections of integrated parental and Oct1 conditional-deficient mouse embryonic stem cells differentiated for six days. Clusters were identified based on gene expression. Relative frequencies are shown. MD lineage-associated clusters are shown in bold.

References (Selected Publications)

  1. Baessler A, Novis CL, Shen Z, Perovanovic J, Wadsworth M, Thiede KA, Sircy LM, Harrison-Chau M, Nguyen NX, Varley KE, Tantin D, Hale JS. (2022) Tet2 coordinates with Foxo1 and Runx1 to balance T follicular helper cell and T helper 1 cell differentiation. Sci Adv. (in press)
  2. Lin Y, Perovanovic J, Kong Y, Igyarto BZ, Zurawski S, Tantin D, Zurawski G, Bettini M, Bettini ML. (2022) Antibody-Mediated Targeting of a Hybrid-Insulin-Peptide Towards Neonatal Thymic Langerin+ Cells Enhances T Cell Central Tolerance and Delays Autoimmune Diabetes. Diabetes (in press)
  3. Sun W, Guo J, McClellan D, Poeschla A, Bareyan D, Casey MJ, Cairns BR, Tantin D*, Engel ME* (2022). GFI1 Cooperates with IKZF1/IKAROS to Activate Gene Expression in T Cell Acute Lymphoblastic Leukemia. Mol Cancer Res 20:501. *co-corresponding authors
  4. Sun W, Jia X, Liesa M, Tantin D*, Ward DM* (2021). ABCB10 Loss Reduces CD4+ T Cell Activation and Memory Formation. J Immunol 208:328. *co-corresponding authors
  5. Kim H, Perovanovic J, Shakya A, Shen Z, German CN, Ibarra A, Jafek JL, Lin N-P, Evavold BD, Chou DH-C, Jensen PE, He X, Tantin D (2021) Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type-1 diabetes. J. Exp. Med. 218:e20200533
  6. Bensard CL, Wisidagama DR, Olson KA, Berg JA, Krah NM, Schell JC, Nowinski SM, Fogarty S, Bott AJ, Wei P, Dove KK, Tanner JM, Panic V, Cluntun A, Lettlova S, Earl CS, Namnath DF, Vázquez-Arreguín K, Villanueva CJ, Tantin D, Murtaugh LC, Evason KJ, Ducker GS, Thummel CS, Rutter J. (2020) Regulation of Tumor Initiation by the Mitochondrial Pyruvate Carrier. Cell Metab. 31: 284
  7. McDonough JE, Ahangari F, Li Q, Jain S, Verleden SE, Herazo-Maya J, Vukmirovic M, DeIuliis G, Tzouvelekis A, Tanabe N, Chu F, Yan X, Verschakelen J, Homer RJ, Manatakis DV, Zhang J, Ding J, Maes K, De Sadeleer L, Vos R, Neyrinck A, Benos PV, Bar-Joseph Z, Tantin D, Hogg JC, Vanaudenaerde BM, Wuyts WA, Kaminski N. (2019) Transcriptional regulatory model of fibrosis progression in the human lung. JCI Insight 4:e141597
  8. Jafek JL, Shakya A, Tai P-Y, Ibarra A, Kim H, Maddox J, Chumley J, Spangrude GJ, Miles RR, Kelley TW and Tantin D (2019) Transcription factor Oct1 protects against hematopoietic stress and promotes acute myeloid leukemia. Exp. Hemat. 76:38
  9. Vázquez-Arreguín K, Bensard C, Schell JC, Swanson E, Chen X, Rutter J, Tantin D (2019) Oct1/Pou2f1 is selectively required for colon regeneration and regulates colon malignancy. PLoS Genet. 15:e1007687
  10. Kim, H, Dickey L, Stone C, Jafek JL, Lane TE, Tantin D (2019) T cell-selective deletion of Oct1 protects animals from autoimmune neuroinflammation while maintaining neurotropic pathogen response. J. Neuroinflamm. 16:133
  11. Shen Z, Formosa T, Tantin D (2018) FACT Inhibition Blocks Induction but not Maintenance of Pluripotency. Stem Cells Dev. 27:1693
  12. Vázquez-Arreguín K, Maddox J, Kang J, Park D, Cano RR, Factor RE, Ludwig T, Tantin D (2018) BRCA1 Through its E3 ligase Activity Regulates the Transcription Factor Oct1 and Carbohydrate Metabolism. Mol. Cancer. Res. 16: 439
  13. Shen Z, Kang J, Shakya A, Tabaka M, Jarboe EA, Regev A, Tantin D (2017) Enforcement of developmental lineage specificity by transcription factor Oct1. Elife e20937
  14. Kikani CK, Wu X, Paul L, Sabic H, Shen Z, Shakya A, Keefe A, Villanueva C, Kardon G, Graves B, Tantin D, Rutter J (2016) Pask integrates hormonal signaling with histone modification via Wdr5 phosphorylation to drive myogenesis. Elife e17985
  15. Vázquez-Arreguín K, Tantin D (2016) The Oct1 transcription factor and epithelial malignancies: old protein learns new tricks. Biochem. Biochim Biophys Acta 1859: 792-804
  16. Shakya A, Goren A, Shalek A, German CN, Snook J, Kuchroo VK, Yosef N, Chan RC, Regev A, Williams MA, Tantin D (2015) Oct1 and OCA-B are Selectively Required for CD4 Memory T Cell Function. J. Exp. Med. 212: 2115
  17. Shakya A, Callister C, Goren A, Yosef N, Garg N, Khoddami V, Nix D, Regev A, Tantin D (2015) Pluripotency transcription factor Oct4 mediates stepwise nucleosome demethylation and depletion. Mol Cell Biol 35: 1014-25
  18. Tantin D (2013) Oct transcription factors in development and stem cells: insights and mechanisms. Development 140: 2857-2866
  19. Maddox J, Tantin D (2013) Oct4, Oct1 and Cancer Stem Cells. In “Cancer Stem Cells” Ed: Vinagolu K. Rajasekhar, Wiley & Sons, p 319–329
  20. Kang J, Shen Z, Lim JM, Handa H, Wells L, Tantin D (2013) Regulation of Oct1/Pou2f1 transcription activity by O-GlcNAcylation. FASEB J. 27: 2807-17
  21. Yosef N, Shalek AK, Gaublomme JT, Jin H, Lee Y, Awasthi A, Wu C, Karwacz K, Xiao S, Jorgolli M, Gennert D, Satija R, Shakya A, Lu DY, Trombetta JJ, Pillai MR, Ratcliffe PJ, Coleman ML, Bix M, Tantin D, Park H, Kuchroo VK, Regev A (2013) Dynamic regulatory network controlling TH17 cell differentiation. Nature 496: 461-468
  22. Manning J, Mitchell B, Appadurai DA, Shakya A, Pierce LJ, Wang H, Nganga V, Swanson PC, May JM, Tantin D, Spangrude GJ (2013) Vitamin C promotes maturation of T-cells. Antioxid Redox Signal 19: 2054-2067
  23. Maddox J, Shakya A, South S, Shelton D, Andersen JN, Chidester S, Kang J, Gligorich KM, Jones DA, Spangrude GJ, Welm BE and Tantin D (2012) Transcription Factor Oct1 is a Somatic and Cancer Stem Cell Determinant. PLoS Genet. 8: e1003048
  24. Li Q, Shakya A, Guo X, Zhang H, Tantin D, Jensen PE, Chen X (2012) Constitutive Nuclear Localization of NFAT in FoxP3+ Regulatory T Cells Independent of Calcineurin Activity. J Immunol 188: 4268-4277
  25. Ferraris L, Stewart AP, Kang J, Desimone AM, Gemberling M, Tantin D, Fairbrother WG (2011) Combinatorial binding of transcription factors in the pluripotency control regions of the genome. Genome Res 21: 1055-1064
  26. Shakya A, Kang J, Chumley J, Williams MA, Tantin D (2011) Oct1 is a switchable, bipotential stabilizer of repressed and inducible transcriptional states. J Biol Chem 286: 450-459
  27. Shakya A, Cooksey R, Cox JE, Wang V, McClain DA, Tantin D (2009) Oct1 loss of function induces a coordinate metabolic shift that opposes tumorigenicity. Nat Cell Biol 11: 320-327
  28. Kang J, Gemberling M, Nakamura M, Whitby FG, Handa H, Fairborther W, Tantin D (2009) A general mechanism for transcription regulation by Oct1 and Oct4 in response to oxidative stress. Genes Dev 23: 208-222
Last Updated: 7/12/22