Toxigenomic Analysis of Nuclear Xenobiotic Receptors

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.  

Publication

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.

PubMedID: 28167773
PubMed Central ID: 

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.

PubMedID: 28096419
PubMed Central ID: 

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.

PubMedID: 27986797

Fan W., Evans R.M.. (2017) Exercise Mimetics: Impact on Health and Performance. Cell Metab. 25:242-247. doi: 10.1016/j.cmet.2016.10.022. PMCID: PMC Journal - In Process

 

PubMedID: 27889389
PubMed Central ID: 

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.

PubMedID: 27106806
PubMed Central ID: 

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.

PubMedID: 27076077
PubMed Central ID: 

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.

PubMedID: 26986782

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. pii: 201525093.

PubMedID: 26858440
PubMed Central ID: 

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.

PubMedID: 26644586

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.  doi: 10.1038/nature16151.

PubMedID: 26580014
PubMed Central ID: 

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.

PubMedID: 26293987

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. pii: molcanres.0204.2015.

PubMedID: 26224368

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.

PubMedID: 25739500
PubMed Central ID: 

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.

PubMedID: 25564661

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. doi: 10.1038/nm.3760.

PubMedID: 25559344

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. doi: 10.1038/nature14304.

PubMedID: 25739500

Fan, W., Evans, R. (2014) PPARs and ERRs: molecular mediators of mitochondrial metabolism. Curr Opin Cell Biol. 33C, 49-54.

PubMedID: 25486445
PubMed Central ID: 

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.

PubMedID: 25404284
PubMed Central ID: 

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, 80-93.

PubMedID: 25259922
PubMed Central ID: 

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.

PubMedID: 25043058
PubMed Central ID: 

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.

PubMedID: 24737872
PubMed Central ID: 

Evans, R. M., Mangelsdorf, D. J. (2014) Nuclear Receptors, RXR, and the Big Bang. Cell. 157(1), 255-66.

PubMedID: 24679540
PubMed Central ID: 

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.

PubMedID: 24619218
PubMed Central ID: 

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.

PubMedID: 24486511
PubMed Central ID: 

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.

PubMedID: 24280961

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.

PubMedID: 24164608
PubMed Central ID: 

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.

PubMedID: 23896737
PubMed Central ID: 

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.

PubMedID: 23653479
PubMed Central ID: 

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.

PubMedID: 23652116
PubMed Central ID: 

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.

PubMedID: 23622244
PubMed Central ID: 

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.

PubMedID: 23159735
PubMed Central ID: 

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, 658-667.

PubMedID: 22371261

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.

PubMedID: 22913318
PubMed Central ID: 

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.  doi: 10.1371/journal.pone.0037705.

PubMedID: 22761658
PubMed Central ID: 

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.

PubMedID: 22310326
PubMed Central ID: 

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.

PubMedID: 22411605
PubMed Central ID: 

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.

PubMedID: 21498392
PubMed Central ID: 

Lamia, K. A., Evans, R. M. (2010) Metabolism: Tick, tock, a beta-cell clock. Nature. 466 (7306), 571-2.

PubMedID: 20671699
PubMed Central ID: 

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), 5223-5228.

PubMedID: 17360356

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.

PubMedID: 17132853

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.

PubMedID: 17132850
PubMed Central ID: 

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, 11323-8.

PubMedID: 16844773

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)

The Salk Institute of Biological Studies
10010 North Torrey Pines Road
La Jolla, CA 92037
P: 858-453-4100, x130
F: 858-455-1349
E-mail: evans@salk.com

Contact

UCSD Superfund Research Center
University of California, San Diego
Pharmacology Department
9500 Gilman Drive, Mail Code 0722
La Jolla, CA 92093-0722