Summary
Superfund site xenobiotics and other environmental toxicants are human health hazards whose toxicity is, in part, associated with altered patterns of gene expression. The goal of this project is to provide molecular mechanisms and models for exposure, focusing on the “classic” xenobiotic receptors (XenRs) PXR and CAR, and their induction of gene networks encoding the Phase I, II and III clearance pathways. Accordingly, to define the chemical space of XenRs in response to environmental toxins, in Aim II we will initiate a comparative chemical library screen using high throughput (HT) cell based luciferase reporter assays. Recently, we have determined that the nuclear receptor ERalpha is capable of responding to anticoagulants, antibacterial and anti-inflammatory drugs thus identifying it as a candidate xenobiotic sensor. Therefore as part of this Aim we will include ERalpha in the above XenRs screen. Some of our HT screens will include extracts gathered from Superfund sites by the Research Translation Core. Comparative gene expression studies will be conducted in Aim II to establish the overlap of ERalpha dependent gene regulation with known PXR and CAR target genes. The in vivo relevance will be established using a humanized hPXR/hCAR reporter mouse. In Aim III we will determine how XenRs control the xenobiotic response at the genome-wide level. Chromatin immunoprecipitation coupled with massively parallel deep sequencing (ChIP-Seq) will be used to identify PXR, CAR and ERalpha cistromes, before and after treatment with high affinity agonists to reveal unique and common (core) xenobiotic networks. The aggregate binding sites will comprise a “xenobiotic cistrome”. Finally, in Aim I, we describe a new HT screening platform called NHR Transcriptional Promoter Ontology which allows us to explore xenobiotic regulation by all human NHRs (+/- ligands) by screening against a panel of ~300 drug metabolism reporter constructs comprised of P450 and conjugation enzyme and transporter sets. This is a unique opportunity to redefine the molecular basis of NHR-xenobiotic regulation and will provide a new roadmap for future study. We will collaborate with the Research Translation Core and Community Engagement Core to share this work with our SRP tribal science partners, industry, EPA, and ATSDR.
Publications
Chen, S., Lu, W., Yueh, M.-F., Rettenmeier, E., Liu, M., Auwerx, J., Yu, R.T., Evans, R.M., Wang, K., Karin, M., Tukey, R.H. (2017) Intestinal NCoR1, a newly discovered regulator of epithelial cell maturation, controls neonatal hyperbilirubinemia. Proc. Nat. Acad. Sci. USA.114:E1432-E1440. doi: 10.1073/pnas.1700232114.
Sherman M.H., Yu R.T., Tseng T.W., Sousa C.M., Liu S., Truitt M.L., He N., Ding N., Liddle C., Atkins A.R., Lebland M., Collisson E.A., Asara J.M., Kimmelman A.C., Downes M., Evans R.M. (2017) Stromal cues regulate the pancreatic cancer epigenome and metabolome. Proc Natl Acad Sci U S A. 114: 1129-1134. doi: 10.1073/pnas.1620164114.
Chung H.K., Ryu D., Kim K.S., Chang J.Y., Kim Y.K., Yi H.-S., Kang S.G., Choi M.J., Lee S.E., Jung S.B., Ryu M.J., Kim S.J., Kweon G.R., Kim H., Hwang J.H., Lee C.-H., Lee S.-J., Wall C.E., Downes M., Evans R.M., Auwerx J., Shong M. (2017) Growth differentiation factor 15 (GDF15) is a myomitokine governing systemic energy homeostasis. J Cell Biol. 216: 149-165. doi: 10.1083/jcb.201607110.
Fan W., Evans R.M.. (2017) Exercise Mimetics: Impact on Health and Performance. Cell Metab. 25:(2)242-247. doi: 10.1016/j.cmet.2016.10.022.
Wall C.E., Yu R.T., Atkins A.R., Downes M., Evans R.M. (2016) Nuclear receptors and AMPK: can exercise mimetics cure diabetes?J Mol Endocrinol. 2016 Apr 22. pii: JME-16-0073. doi: 10.1530/JME-16-0073.
Yoshihara E., Wei Z., Lin C.S., Fang S., Ahmadian M., Kida Y., Tseng T., Dai Y., Yu R.T., Liddle C., Atkins A.R., Downes M., Evans R.M. (2016) ERRγ Is Required for the Metabolic Maturation of Therapeutically Functional Glucose-Responsive β Cells.Cell Metab. 23:622-34. doi: 10.1016/j.cmet.2016.03.005.
Booth D., Ding N., Parnell G., Shahijanian F., Coulter S., Schibeci S., Atkins A., Stewart G., Evans R.M., Downes M., Liddle C. (2016) Cistromic and genetic Evidence that the Vitamin D Receptor mediates Susceptibility to latitude-dependent Autoimmune Diseases.17:213-9. doi: 10.1038/gene.2016.12.
Liu, W., Struik, D., Nies, V. J., Jurdzinski, A., Harkema, L., de Bruin, A., Verkade, H. J., Downes, M., Evans, R. M., van Zutphen, T., Jonker, J. W. (2016) Effective treatment of steatosis and steatohepatitis by fibroblast growth factor 1 in mouse models of nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A. 113(8):2288-93. doi: 10.1073/pnas.1525093113. Epub 2016 Feb 8.
Ding N., Hah N., Yu RT., Sherman M.H., Benner C., Leblanc M., He M., Liddle C., Downes M., and Evans RM. (2015) BRD4 is a novel therapeutic target for liver fibrosis. Proc Nat Sci USA. 112: 15713-8.
Bapat, S. P., Myoung Suh, J., Fang, S., Liu, S., Zhang, Y., Cheng, A., Zhou, C., Liang, Y., LeBlanc, M., Liddle, C., Atkins, A. R., Yu, R. T., Downes, M., Evans, R. M., Zheng, Y. (2015) Depletion of fat-resident Treg cells prevents age-associated insulin resistance. Nature. 528(7580):137-41. doi: 10.1038/nature16151.
Ranjit, S., Dvornikov, A., Stakic, M., Hong, S. H., Levi, M., Evans, R. M., Gratton, E. (2015) Imaging Fibrosis and Separating Collagens using Second Harmonic Generation and Phasor Approach to Fluorescence Lifetime Imaging. Sci Rep. 5:13378. doi: 10.1038/srep13378.
Arensman, M. D., Nguyen, P., Kershaw, K. M., Lay, A. R., Ostertag-Hill, C. A., Sherman, M. H., Downes, M., Liddle, C., Evans, R. M., Dawson, D. W. (2015) Calcipotriol Targets LRP6 to Inhibit Wnt Signaling in Pancreatic Cancer. Mol Cancer Res. 13(11):1509-19. doi: 10.1158/1541-7786.MCR-15-0204.
Suh, J. M., Jonker, J. W., Ahmadian, M., Goetz, R., Lackey, D., Osborn, O., Huang, Z., Liu, W., Yoshihara, E., van Dijk, T. H., Havinga, R., Fan, W., Yin, Y. Q., Yu, R. T., Liddle, C., Atkins, A. R., Olefsky, J. M., Mohammadi, M., Downes, M., Evans, R. M. (2015) Corrigendum: Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature. 520(7547), 388. doi: 10.1038/nature14304.
Hah, N., Benner, C., Chong, L. W., Yu, R. T., Downes, M., Evans, R. M. (2015) Inflammation-sensitive super enhancers form domains of coordinately regulated enhancer RNAs. Proc Natl Acad Sci U S A. 112(3). E297-302.
Fang, S., Suh, J. M., Reilly, S. M., Yu, E., Osborn, O., Lackey, D., Yoshihara, E., Perino, A., Jacinto, S., Lukasheva, Y., Atkins, A. R., Khvat, A., Schnabl, B., Yu, R. T., Brenner, D. A., Coulter, S., Liddle, C., Schoonjans, K., Olefsky, J. M., Saltiel, A. R., Downes, M., Evans, R. M. (2015) Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med. 21(2):159-65. doi: 10.1038/nm.3760.
Suh, J.M., Jonker, J. W., Ahmadian, M., Goetz, R., Lackey, D., Osborn, O., Huang, Z., Liu, W., Yoshihara, E., van Dijk, T. H., Havinga, R., Fan, W., Yin, Y. Q., Yu, R. T., Liddle, C., Atkins, A. R., Olefsky, J. M., Mohammadi, M., Downes, M., Evans, R. M. (2014) Corrigendum: Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature. 520(7547):388. doi: 10.1038/nature14304.
Fan, W., Evans, R. (2014) PPARs and ERRs: molecular mediators of mitochondrial metabolism. Curr Opin Cell Biol. 33:49-54. doi: 10.1016/j.ceb.2014.11.002.
Yueh, M. F., Taniguchi, K., Chen, S., Evans, R. M., Hammock, B. D., Karin, M., Tukey, R. H. (2014) The commonly used antimicrobial additive triclosan is a liver tumor promoter. Proc Natl Acad Sci USA. 111(48):17200-5. doi: 10.1073/pnas.1419119111.
Sherman, M. H., Yu, R. T., Engle, D. D., Ding, N., Atkins, A. R., Tiriac, H., Collisson, E. A., Connor, F., Van Dyke, T., Kozlov, S., Martin, P., Tseng, T. W., Dawson, D. W., Donahue, T. R., Masamune, A., Shimosegawa, T., Apte, M. V., Wilson, J. S., Ng, B., Lau, S. L., Gunton, J. E., Wahl, G. M., Hunter, T., Drebin, J. A., O'Dwyer, P. J., Liddle, C., Tuveson, D. A., Downes, M., Evans, R. M. (2014) Vitamin d receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell. 159(1):80-93. doi: 10.1016/j.cell.2014.08.007.
Suh, J. M., Jonker, J. W., Ahmadian, M., Goetz, R., Lackey, D., Osborn, O., Huang, Z., Liu, W., Yoshihara, E., van Dijk, T. H., Havinga, R., Fan, W., Yin, Y. Q., Yu, R. T., Liddle, C., Atkins, A. R., Olefsky, J. M., Mohammadi, M., Downes, M., Evans, R. M. (2014) Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature. doi: 10.1038/nature13540.
Zhao, X., Cho, H., Yu, R. T., Atkins, A. R., Downes, M., Evans, R. M. (2014) Nuclear receptors rock around the clock. EMBO Rep. 15(5):518-28. doi: 10.1002/embr.201338271.
Evans, R. M., Mangelsdorf, D. J. (2014) Nuclear Receptors, RXR, and the Big Bang. Cell. 157(1):255-66. doi: 10.1016/j.cell.2014.03.012.
Hong, S. H., Ahmadian, M., Yu, R. T., Atkins, A. R., Downes, M., Evans, R. M. (2014) Nuclear receptors and metabolism: from feast to famine. Diabetologia. 57(5):860-7. doi: 10.1007/s00125-014-3209-9.
d'Uscio, L. V., He, T., Santhanam, A. V., Tai, L. J., Evans, R. M., Katusic, Z. S. (2014) Mechanisms of vascular dysfunction in mice with endothelium-specific deletion of the PPAR-δ gene. Am J Physiol Heart Circ Physiol. 306(7):H1001-10. doi: 10.1152/ajpheart.00761.2013.
Fan, W., Atkins, A. R., Yu, R. T., Downes, M., Evans, R. M. (2013) Road to exercise mimetics: targeting nuclear receptors in skeletal muscle. J Mol Endocrinol. 51(3):T87-T100. doi: 10.1530/JME-13-0258.
Ding, N., Liddle, C., Evans, R. M., Downes, M. (2013) Hepatic actions of vitamin D receptor ligands: a sunshine option for chronic liver disease? Expert Rev Clin Pharmacol. 6(6):597-9. doi: 10.1586/17512433.2013.841078.
Kittayaruksakul, S., Zhao, W., Xu, M., Ren, S., Lu, J., Wang, J., Downes, M., Evans, R. M., Venkataramanan R, Chatsudthipong V, Xie W. (2013) Identification of three novel natural product compounds that activate PXR and CAR and inhibit inflammation. Pharm Res. 30(9):2199-208. doi: 10.1007/s11095-013-1101-9.
Du, L., Bergsneider, M., Mirsadraei, L., Young, S. H., Jonker, J. W., Downes, M., Yong, W. H., Evans, R. M., Heaney, A. P. (2013) Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease. Proc Natl Acad Sci USA. 110(21):8555-60. doi: 10.1073/pnas.1306182110.
Ahmadian, M., Suh, J. M., Hah, N., Liddle, C., Atkins, A. R., Downes, M., Evans, R. M. (2013) PPARγ signaling and metabolism: the good, the bad and the future. Nat Med. 19(5):557-66. doi: 10.1038/nm.3159.
Ding, N., Yu, R. T., Subramaniam, N., Sherman, M. H., Wilson, C., Rao, R., Leblanc, M., Coulter, S., He, M., Scott, C., Lau, S. L., Atkins, A. R., Barish, G. D., Gunton, J. E., Liddle, C., Downes, M., Evans, R. M. (2013) A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell. 153(3):601-13. doi: 10.1016/j.cell.2013.03.028.
Uhlenhaut, N. H., Barish, G. D., Yu, R. T., Downes, M., Karunasiri, M., Liddle, C., Schwalie, P., Hübner, N., Evans, R. M. (2013) Insights into negative regulation by the glucocorticoid receptor from genome-wide profiling of inflammatory cistromes. Mol Cell. 49(1):158-71. doi: 10.1016/j.molcel.2012.10.013.
Chen, S., Yueh, M. F., Evans, R. M., Tukey, R. H. (2012) Pregnane-x-receptor controls hepatic glucuronidation during pregnancy and neonatal development in humanized UGT1 mice. Hepatology. 56(2):658-67. doi: 10.1002/hep.25671.
Li, T., Yu, R. T., Atkins, A. R., Downes, M., Tukey, R. H., Evans, R. M. (2012) Targeting the pregnane X receptor in liver injury. Expert Opin Ther Targets. 16(11):1075-83. doi: 10.1517/14728222.2012.715634.
Yueh, M. F., Li, T., Evans, R. M., Hammock, B., Tukey, R. H. (2012) Triclocarban mediates induction of xenobiotic metabolism through activation of the constitutive androstane receptor and the estrogen receptor alpha. PLoS One. 7(6):e37705. doi: 10.1371/journal.pone.0037705.
Noreault-Conti, T. L., Fellows, A., Jacobs, J. M., Trask, H. W., Strom, S. C., Evans, R. M., Wrighton, S. A., Sinclair, P. R., Sinclair, J. F., Nichols, R. C. (2012) Arsenic decreases RXRα-dependent transcription of CYP3A and suppresses immune regulators in hepatocytes. Int Immunopharmacol. 12(4):651-6. doi: 10.1016/j.intimp.2012.01.008.
Fan, W., Downes, M., Atkins, A., Yu, R., Evans, R. M. (2011) Nuclear receptors and AMPK: resetting metabolism. Cold Spring Harb Symp Quant Biol. 76:17-22. doi: 10.1101/sqb.2012.76.010470.
Kacevska, M., Downes, M. R., Sharma, R., Evans, R. M., Clarke, S. J., Liddle, C., Robertson, G. R. (2011) Extrahepatic cancer suppresses nuclear receptor-regulated drug metabolism. Clin Cancer Res. 17(10):3170-80. doi: 10.1158/1078-0432.CCR-10-3289.
Lamia, K. A., Evans, R. M. (2010) Metabolism: Tick, tock, a beta-cell clock. Nature. 466(7306):571-2. doi: 10.1038/466571a.
Sonoda, J., Mehl, I. R., Chong, L. W., Nofsinger, R. R., Evans, R. M. (2007) PGC-1beta controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis. Proc Natl Acad Sci USA. 104(12):5223-8. doi: 10.1073/pnas.0611623104.
Germain, P., Chambon, P., Eichele, G., Evans, R. M., Lazar, M. A., Leid, M., De Lera, A. R., Lotan, R., Mangelsdorf, D. J., Gronemeyer, H. (2006) Pharmacol Rev. 58(4), 760-72.
Germain, P., Chambon, P., Eichele, G., Evans, R. M., Lazar, M. A., Leid, M., De Lera, A. R., Lotan, R., Mangelsdorf, D. J., Gronemeyer H. (2006) International Union of Pharmacology. LX. Retinoic acid receptors. Pharmacol Rev. 58(4), 712-25. doi: 10.1124/pr.58.4.4
Stedman, C., Liddle, C., Coulter, S., Sonoda, J., Alvarez, J. G., Evans, R. M., and Downes, M. (2006) Benefit of FXR inhibition in obstructive cholestasis. Proc Natl Acad Sci USA. 103(30):11323-8. doi: 10.1073/pnas.0604772103
Main Contact Information
Project Leader
- Dr. Ronald M. Evans
Professor and Director
Gene Expression Laboratory
Howard Hughes Medical Institute Investigator
March of Dimes Chair in Molecular and Developmental Biology
Superfund Related Project Members
- Christi Brondos, Administrator
- Lita Ong, Lab Manager
- Xuan Zhao, Senior Research Associate
- Ning Ding, Post-Doctoral Scholar
- Benson Lu, Post-Doctoral Scholar
- Chun Shi (Ryan) Lin, Post-Doctoral Scholar
- Ruth Yu, Staff Researcher
Resources
Dr. Ron M. Evans, Ph.D., Salk Institute of Biological Sciences
UCSD Division of Biological Sciences
UCSD Biomedical Sciences Graduate Program
Howard Hughes Medical Institute (HHMI)
References From PubMed (NCBI)
Contact
UCSD Superfund Research Center
University of California, San Diego
Pharmacology Department
9500 Gilman Drive, Mail Code 0722
La Jolla, CA 92093-0722