You are here:

Dean Tantin

Associate Professor of Microbiology and Immunology

Dean Tantin

B.S. University of California, San Diego

Ph.D. University of California, Los Angeles



Dean Tantin's Lab Page

Dean Tantin's PubMed Literature Search


Molecular Biology Program

Gene Regulation in Mammals


The major long-term goal of our research is to understand the transcriptional underpinnings of immune responses, stem cell function and the malignant state. Sequence-specific DNA binding transcription factors sculpt gene expression patterns by interacting with particular DNA sequences in our genomes. We use biochemical, genetic and genomic approaches to determine mechanisms and functions of these factors. Our work is highly interdisciplinary and involves the fields of immunology, stem cell biology, transcription and chromatin, metabolism and malignancy.

Gene regulatory basis of CD4 T cell memory
Oct1 controls target gene expression through related mechanisms that enforce either a repressed transcription state, or a silent but "poised" state. Poised gene expression states are indicative of both memory lymphocytes and stem cells. Interestingly, Oct1 controls CD4 T memory cell formation and activity. Oct1 is widely expressed but one of its cofactors, OCA-B, is induced in CD4 T cells upon activation. We found that T cell-specific OCA-B loss also compromises CD4 T memory cell formation and activity. We are studying if OCA-B overexpression can drive cells into a memory phenotype, and if OCA-B expression can be used to prospectively identify CD4 memory cells during ongoing immune responses. We have developed OCA-B inhibitors, and will test their ability block memory formation. We are also interested in the role of these activities in CD8 T cells, and the ability of these proteins to coordinately regulate distant target genes by spatially localizing them together.

Role of OCA-B in autoimmunity
The development of new treatments that block autoimmunity while preserving normal immune function constitutes a major long-term goal in the field. Our transcriptional work has identified a mechanism operating at a set of ~150 immunomodulatory target genes in CD4+ T cells, including Il2, Ifng and Il17a. Upon T cell activation, many of these same genes are activated by NF-AT, AP-1 and NF-kB. These transcription factors can be thought of as the primary on/off switches for these genes, and calcineurin inhibitors for example effectively shut down their expression in T cells. Such drugs can be thought of as potent “sledgehammers” and have utility in many contexts, but also have drawbacks including global dampening of immune function and side effects due to the activity of these factors in other tissues. Because the new mechanism we identified only controls gene expression in cases of repeated antigen exposure, we envision that targeting this pathway will be analogous to a precision “scalpel” in which over-active, pathogenic T cell responses are selectively inhibited. Moreover, expression of the central component of this pathway, a transcription cofactor known as OCA-B, is almost entirely restricted to lymphocytes. Studies associate polymorphisms in binding sites for Oct1, the transcription factor with which OCA-B docks, with a variety of autoimmune diseases including type-1 diabetes (T1D), celiac disease, rheumatoid arthritis and multiple sclerosis (MS). We have developed genetic and pharmaceutical tools that allow us to interrogate this pathway in laboratory mice, with the former showing efficacy in MS models and the latter showing efficacy in T1D models.

Control of developmentally inducible gene expression in differentiating embryonic stem cells
The embryonic stem cell master transcription regulator Oct4 is a potent controller of pluripotency. Oct4 associates with targets that directly control pluripotency (such as the gene encoding Oct4 itself), and with developmentally inducible genes that are poised--silent but held in a configuration that allows them to be readily activated, or stably repressed, later in development. We are studying the role of the co-expressed Oct4 paralogs (e.g., Oct1) at these targets. These proteins have similar in vitro DNA binding specificity as Oct4 and recognize many of the same target genes. We have found that pluripotent cells with inducible Oct1 knockout behave normally until differentiation, where they fail to induce developmentally appropriate genes, and aberrantly express developmentally inappropriate genes. Upon ESCs differentiation, Oct1 occupies Oct4 target genes, sometimes transiently. These results support a “handoff mode”, whereby activities related to Oct4 take over gene poising and gene silencing duties from Oct4 as cells differentiate and Oct4 is lost. We are determining whether this occurs genome-wide, and identifying the cofactors used in this process.

Requirement for FACT in the induction but not maintenance of pluripotency
We previously showed that FACT is transiently recruited to pluripotency-associated target genes by newly-bound Oct4 to mediate nucleosome depletion, suggesting that FACT may be required for pluripotency generation but not maintenance. To test this hypothesis, we targeted FACT with CRISPR and chemical inhibition, and monitored induction and maintenance of pluripotency. We found that FACT inhibition blocked the induction of pluripotency without affecting the viability, proliferation, undifferentiated state, or core pluripotency gene expression of established embryonic stem cells or induced pluripotent stem cells. FACT is required for an early step in reprogramming. Trypsinization and passage of pluripotent cells transiently re-introduces a requirement for FACT. While FACT has been considered an essential transcription factor, these results contribute to the emerging view that it instead promotes transitions between stable profiles including reprogramming to pluripotency, but it is dispensable for the growth and survival of fibroblasts and un-passaged pluripotent cells.

Reciprocal control of BRCA1 protein stability by Oct1
Oct1 is widely expressed, but more highly expressed in somatic and cancer stem cell compartments, where it promotes glycolytic metabolic phenotypes. Interestingly mRNA levels remain unchanged. We found that Oct1 protein is destabilized by BRCA1/BARD1 via its N-terminal E3 ligase activity. Interestingly, we have found that Oct1 reciprocally controls BRCA1 protein levels through a post-transcriptional mechanism that is invisible to high-throughput techniques. We are working to identify the mechanism.

Contribution of Oct1 to tissue regeneration and malignancy
Oct protein is elevated in multiple tumor types. It promotes oncogenic transformation and its loss protects mice in several tumor models. In normal cells Oct1 is a somatic and cancer stem cell determinant. It promotes these functions through multiple pathways including control of cellular metabolism. We have found that Oct1 is dispensable for reconstitution of the blood system by hematopoietic stem cells, but is required in the case of serial or competitive transplants. In the gut, we have found that Oct1 is dispensable for normal homeostasis but required for regeneration. We are working to understand the molecular basis of these phenomena, and are determining the role of Oct1 and cofactors in mouse models of leukemia and colon cancer.



Embryonic stem cells carrying a conditional allele of Oct1 were injected into blastocysts to generate chimeric animals (left). Treatment of these cells with tamoxifen to delete Oct1 results in a normal embryonic cell ground state, but lack of contribution to adult tissues (right).

Selected References

  1. Shen Z, Formosa T, Tantin D (2018) FACT Inhibition Blocks Induction but not Maintenance of Pluripotency. Stem Cells Dev. In press
  2. 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

  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. Tantin D (2013) Oct transcription factors in development and stem cells: insights and mechanisms. Development 140: 2857-2866
  9. Maddox J, Tantin D (2013) Oct4, Oct1 and Cancer Stem Cells. In “Cancer Stem Cells” Ed: Vinagolu K. Rajasekhar, Wiley & Sons, p 319–329
  10. 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
  12. 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
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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

to page top

Last Updated: 12/7/18