Research Area:Ìý Cell and Molecular Biology

Research Description:

My laboratory studies the mechanisms and physiological consequences of regulation of gene transcription by nuclear receptors, in particular the vitamin D receptor (VDR). The lab’s work has focused largely on the non-classical physiological actions of vitamin D, whose biologically active form, 1,25-dihydroxyvitamin D (1,25D), controls the ligand-dependent transcriptional regulation functions of the VDR. My group has extensive experience in several molecular genetics and genomics techniques. We performed the first large-scale gene expression profiling studies of 1,25D signaling. Collectively, these studies identified over 1,000 vitamin D target genes and vastly expanded our knowledge of 1,25D-regulated gene expression. They provided numerous insights into actions of 1,25D, in particular its capacity to regulate cell proliferation and differentiation and its role in immune system regulation. Notably, they led to the discovery that the 1,25D-bound VDR recruits Sirtuin 1 deacetylase to activate of FoxO protein tumor suppressor proteins and induce cell cycle arrest. We also found that vitamin D signaling is a master regulator of expression and function of the oncogenic transcription factor cMYC and its antagonist MXD1. 1,25D signaling leads to suppression of cMYC function by multiple mechanisms. Notably, the 1,25D-bound VDR suppresses cMYC function in part via using the tumor suppressor and E3 ligase FBW7 as a cofactor to accelerate the proteasomal turnover of cMYC and other cell cycle drivers.

Our early studies also revealed numerous 1,25D target genes whose products are implicated in immune system function. This led to our discovery of consensus binding sites for the VDR (vitamin D response elements) in the regulatory regions of human genes encoding antimicrobial peptides, DEFB4/HBD2 and CAMP, two of the body’s natural antibiotics. We showed that expression of both genes was induced and that treatment of cells with 1,25D led to secretion of anti-bacterial activity. This paper opened the field of study of 1,25D as an inducer of innate immunity in humans. It was highlighted in an article in Scientific American (translated into 12 at least languages). We also discovered that 1,25D stimulates the NOD2 -> DEFB4 innate immune pathway, whose compromised function is associated with increased risk of Crohn’s disease (CD).

Recent work has linked vitamin D signaling to molecular events in the thymus that are fundamental for prevention of autoimmunity. The thymus is an organ that is essential for elimination of self-reactive T cells. The lab showed that the critical thymic protein AIRE, whose absence leads to a condition called APECED, characterized by multiple autoimmune conditions, is a cofactor of the vitamin D receptor. Intriguingly, loss of vitamin D signaling impairs normal thymic development and AIRE function and leads to premature thymic aging. These findings provide a compelling molecular basis for several clinical studies linking vitamin D deficiency early in life to increased risk of autoimmunity.

Education: B.Sc. (Biochemistry), MSc. (Chemistry), Carleton University, Ph.D. (Biochemistry), Harvard University

Selected Publications:

Artusa, P. and White, J.H. (2025) Vitamin D and its analogues in immune system regulation. Pharmacological Reviews

Artusa, P., Nguyen-Yamamoto, L., Barbier, C., Aghazadeh Habash, Y., Ismailova, A., Lebel, M.-E., Salehi-Tabar, R., Ragoussis, I., Goltzman, D., Melichar, H. and White, J.H. (2024) Skewed epithelial morphogenesis and premature aging of the thymus in the absence of vitamin D signaling. Science Adv. 10, eadm9582.

Artusa, P., Lebel, M.-E., Memari, B., Salehi-Tabar, R., Barbier, C., Karabatsos, S., Ismailova, A., Melichar, H. and White, J.H. (2023) Cutting Edge: Aire is a coactivator of the vitamin D receptor. J. Immunol. 211, 175-179.

Dimitrov, V., Barbier, C., Ismailova, A., Wang, Y., Dmowski, K., Salehi-Tabar, R., Memari, B., Groulx-Boivin, E. and White, J.H. (2021) Vitamin D-regulated gene expression profiles: species-specificity and cell-specific effects on metabolism and immunity. Endocrinology 162, bqaa218. .

Salehi-Tabar, R., Memari, B., Wong, H. Rochel, N. and White, J.H. (2019) The E3 ligase FBW7 and the vitamin D receptor are mutual cofactors in protein turnover and transcriptional regulation. Mol. Cancer Res. 17, 709-719.

Bouttier, M., Laperriere, D., Memari, B., Verway, M., Mitchell, E., Wang, T.T., Behr, M., Sladek, R., Mader, S. and White, J.H. (2016) Alu repeats as transcriptional regulatory platforms in macrophage responses to M. tuberculosis infection. Nucl. Acid. Res. doi: 10.1093/nar/gkw782.

Verway, M., Bouttier, M., Wang, T.T., Carrier, M., Calderon, M., An, B.-S., Devemy, E., McIntosh, F., Divangahi, M., Behr, M.A. and White, J.H. (2013) Vitamin D induces interleukin-1b expression: Paracrine macrophage-epithelial signaling controls M. tuberculosis infection. PLoS Pathogens 9(6): e1003407.

Salehi-Tabar, R., Nguyen-Yamamoto, L., Tavera-Mendoza, L.E., Quail, T., Dimitrov, V., An, B.-S., Glass, L., Goltzman, D. and White, J.H. (2012) The vitamin D receptor as a master regulator of the cMYC/MXD1 network. Proc. Nat. Acad. Sci. U.S.A. 109, 18827-32.

Wang, T.T, Dabbas, B., Laperriere, D., Bitton, A., Tavera-Mendoza, L.E., Soualhine, H., Dionne, S., Servant, M.J., Bitton, A., Seidman, E., Mader, S., Behr, M. and White, J.H. (2010) Direct and indirect induction by 1,25-dihydroxyvitamin D₃ of the NOD2/CARD15-beta defensin 2 innate immune pathway defective in Crohn’s disease. J. Biol. Chem. 285, 2227 – 2231.

An, B.-S., Tavera-Mendoza, L.E., Dimitrov, V., Wang, X., Calderon, M., Wang, H.-J., and White, J.H. (2010) Stimulation of SIRT1-regulated FoxO protein function by the ligand-bound vitamin D receptor. Mol. Cell. Biol. 30, 4890-4900.

Tavera-Mendoza, L.E., Quach, T., Dabbas, B., Hudon, J., Liao, X., Palijan, A., Gleason, J.L., and White, J.H. (2008) Incorporation of histone deacetylase inhibition into the structure of a nuclear receptor agonist. Proc. Nat. Acad. Sci. U.S.A. 105, 8250-55.

Tavera-Mendoza, L. and White, J.H. (2007) Cell defenses and the sunshine vitamin. Scientific American. November, 297, 62-72.

Wang, T.T., Tavera-Mendoza, L., Laperriere, D., Nagai, Y., Burton MacLeod, N., Libby, E., Zhang, R., Bourdeau, V., Konstorum, A., Lallemant, B., Mader, S. and White, J.H. (2005) Large-scale in silico and microarray-based genomic screening of 1,25-dihydroxyvitamin D₃ target genes. Mol. Endocrinol. 19, 2685-95.

Wang, T.T., Nestel, F., Bourdeau, V., Nagai, Y., Wang, Q., Wu, J., Tavera-Mendoza, L., Lin, R., Hanrahan, J.W., Mader, S. and White, J.H. (2004) Cutting Edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J. Immunol. 173, 2909-12.

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