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Developmental Regulation of the Drug-Processing Genome

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DEVELOPMENTAL REGULATION OF THE DRUG-PROCESSING GENOME IN MOUSE LIVER By Julia Yue Cui B.S., Chukechen Honors College, Zhejiang University, 2005 Submitted to the Graduate Degree Program in Pharmacology, Toxicology, and Therapeutics and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy Dissertation Committee Curtis Klaassen, Ph.D. (Chair) Yu-Jui Yvonne Wan, Ph.D. Bruno Hagenbuch, Ph.D. Grace Guo, Ph.D. Lane Christenson, PhD. Date defended: The Dissertation Committee for Julia Yue Cui certifies that this is the approved version of the following dissertation: DEVELOPMENTAL REGULATION OF THE DRUG-PROCESSING GENOME IN MOUSE LIVER Dissertation Committee Curtis Klaassen, Ph.D. (Chair) Yvonne Wan, Ph.D. Bruno Hagenbuch, Ph.D. Grace Guo, Ph.D. Lane Christenson, PhD. Date approved: ii ACKNOWLEDGEMENTS I would like to acknowledge my dissertation committee, Drs. Curtis Klaassen, Yu-Jui Yvonne Wan, Bruno Hagenbuch, Grace Guo, and Lane Christenson for their insightful suggestions and constructive criticisms to improve my dissertation. I am very grateful to my academic father, Dr. Curtis Klaassen, for introducing me to the world of toxicology, for his guidance and enthusiasm in my research, and endless support of my PhD studies. He always encourages me to do the most and best I can for my career. From him, not only have I learnt how to do good science, but also how to be a good scientist and educator. He is the person I trust the most in my career, the person I find confidence from always, and the person I will be eternally grateful for the rest of my life. I would like to acknowledge all the faculty members of the Department of Pharmacology, Toxicology, and Therapeutics for their help and advice. I would like to especially thank Dr. Thomas Pazdernik for his help with my course work. I would like to thank all the present and past members in Dr. Curtis Klaassen’s laboratory for their help and contribution to my research, especially Drs. Lauren Aleksunes, Yuji Tanaka, Xingguo Cheng, and Cheryl Rockwell. I would also like to acknowledge Dr. Sumedha Gunewardena from the Kansas Intellectual and Developmental Disabilities Research Center, who has collaborated with me on one of my research projects. I would like to acknowledge all the department staff and my fellow graduate students for their generous assistance during the past five years. iii TABLE OF CONTENTS Chapter I. General introduction and background………………………………….1 Chapter II. Statement of purpose...………………………………………………….40 Chapter III. Experimental materials and methods……………………43 Chapter IV. Global picture of the ontogeny of critical drug-processing genes and regulatory factors in liver development……………………...…...67 Chapter V. The ontogeny of novel cytochrome P450 gene isoforms during postnatal liver maturation in mice..........………….……...…………..87 Chapter VI. Genetic and epigenetic regulation and expression signatures of glutathione S-transferases in developing mouse liver …………....127 Chapter VII. Developmental regulation of liver transporters in mice Part I. Bile acids via FXR initiate the expression of major transporters involved in the enterohepatic circulation of bile acids in newborn mice …….…………………………………………………………..…....157 Part II. Regulation of xenobiotic transporters by PXR..……………………...198 Chapter VIII. Ontogenic regulation of transcription factors Ahr, PPARα and PGC-1α in mouse liver………………………………………………212 Chapter IX. General summary and conclusions...……………………….……..259 Chapter X. References………………..……………………………………….....263 Appendices………………………..…………………………………………………297 iv LIST OF ABBREVIATIONS Abbreviation Full name Abcg5 ATP binding cassette g5 Abcg8 ATP binding cassette g8 AhR Aryl hydrocarbon receptor Aldh Aldehyde dehydrogenase ARNT AhR nuclear translocator Asbt Apical sodium-dependent bile acid transporter Bcrp Breast cancer resistance protein bDNA Branched DNA Bsep Bile-salt export pump CA Cholic acid CAR Constitutive androstane receptor ChIP Chromatin immunoprecipitation Chr Chromosome Cnt Concentrative nucleoside transporter Cyp Cytochrome P450 enzymes DCA Deoxycholic acid EHC Enterohepatic circulation Ent Equilibrative nucleoside transporter Fgf15 Fibroblast growth factor 15 FgfR4 Fibroblast growth factor receptor 4 FXR Farnesoid X receptor GADD45 Growth arrest and DNA damage Gapdh Glyceraldehyde-3-phosphate dehydrogenase Gst Glutathione S-transferase H3K27Me3 Trimethylation of H3 at lysine-27 H3K4Me2 Dimethylation of histone H3 at lysine-4 IGB Integrated genome browser HSP90 Heat shock protein 90 LC-MS Liquid chromatography-mass spectrometry LCA Lithocholic acid lit/lit mice Mice with a spontaneous mutation in the growth-hormone releasing-hormone receptor Mate Multidrug and toxin extrusion protein MCA Muricholic acid Mdr Multidrug resistance protein Mrp Multidrug resistance-associated protein NcoR1 Nuclear receptor co-repressor 1 Nrf2 Nuclear factor erythroid 2-related factor 2 Ntcp Na+-taurocholate cotransporting polypeptide Oat Organic anion transporter Oatp Organic anion transporting polypeptide Oct Organic cation transporter Ost Organic solute transporter RT-qPCR Reverse transcription-quantitative polymerase chain reaction PGC-1 Peroxisome proliferator-activated-γ coactivator 1 PPAR Peroxisome proliferator-activated receptor PXR Pregnane X receptor RLU Relative light units RXR Retinoid-X-receptor SHP Small heterodimer partner SRC-1 Steroid receptor coactivator-1 Sult Sulfotransferase TAS Affymetrix Tiling Analysis Software T-BA Taurine-conjugated bile acid TR Thyroid hormone receptor v Abbreviation Full name (Cont’d) TSS Transcriptional start site UDCA Ursodeoxycholic acid Ugt UDP-glucuronosyltransferase UTR Untranslated region VDR Vitamin D receptor (Gonzalez et al., 1986; Omiecinski et al., 1990; Krauer and Dayer, 1991; Pineau et al., 1991; Tee et al., 1992; Bammler et al., 1994; Girard et al., 1994; Hayes and Pulford, 1995; Board et al., 1997; Hakkola et al., 1998; Knapen et al., 1999; Raijmakers et al., 2001; Bird, 2002; Buist et al., 2002; Kliewer et al., 2002; Li et al., 2002; Satoh et al., 2002; Slitt et al., 2002; Sonoda et al., 2002; Jaenisch and Bird, 2003; Zielinska et al., 2004; Bernstein et al., 2005; Boyer et al., 2006; Hawkins and Ren, 2006; Johnson et al., 2006; Lee et al., 2006; Roh et al., 2006; Barski et al., 2007; Kiefer, 2007; Knight et al., 2007; Kouzarides, 2007; Reik, 2007; Knight et al., 2008; Yijia et al., 2008; Cui et al., 2009b; Townsend et al., 2009; Yeager et al., 2009) vi LIST OF TABLES Table 1.1. List of critical drug-processing genes and transcription factors in liver.........11 Table 1.2. List of subfamily members of nuclear receptors............................................17 Table 1.3. Some transcriptional activating and repressing histone modifications..........31 Table 3.1. The human homologs for the mouse Cyps (if present), as well as their DNA and protein identities.……..…….……..…………………………………..45 Table 3.2. The Cyp gene names, accession numbers, and the panel information for the multiplex branched amplification technology…...…….………………..48 Table 3.3. Cyp gene names, accession numbers, and the forward and reverse primer sequences for RT-PCR….……..………………………………………..50 Table 3.4. Oligonucleotide probes generated for analysis of mouse FXR and SHP mRNA by bDNA.…..….…………………………………………………….54 Table 6.1. Consensus PXR-DNA binding motifs within the ChIP-DNA sequences for PXR...…..…...………………………………………………………………..143 vii LIST OF FIGURES Figure 1.1. Illustration of phase-I and -II drug metabolism as well as transporters in liver………………………………………………………………………………...2 Figure 1.2. The hierarchy of organization from chromosome to nucleosome................27 Figure 4.1. Developmental expression of drug-processing genes in mouse liver……..69 Figure 4.2. The ontogeny of transcription factors in mouse liver during development...71 Figure 4.3. Relative enrichment of epigenetic marks (H3K4Me2, H3K27Me3, and DNAMe) on representative chromosomes (chr5, 12, and 15) during mouse liver development…….………………...……………………………….73 Figure 4.4. Western blot of tissue distribution of H3K4Me2 (A) as well as immunofluorescence staining of H3K4Me2 during mouse liver development (B)……………………………………………………………..….74 Figure 4.5. A roadmap of enrichment in hepatic PXR-DNA binding in the entire mouse genome………………………….……………………………………….76 Figure 4.6. Motif analysis of PXR-DNA binding profiles in mouse liver………………....78 Figure 4.7. A diagram of the helical turns of DNA and the formation of DR-(5n+4) like DNA motifs……………………………………………………………………….80 Figure 4.8. Quantification of PXR binding to DR-(5n+4)-like DNA sequences by ELISA-based transcription factor binding assays……………….……………83 Figure 4.9. An overlay between PXR-DNA binding and presence of three epigenetic marks (H3K4Me2, H3K27Me3, and DNAMe) on representative chromosomes (chr5, 12, and 15) in mouse liver…….…………………….....85 Figure 5.1. Genomic locations of Cyp gene cluster within the first 4 families..…………95 Figure 5.2. The mRNA ontogenic expression of the Cyp1 family (Cyp1a1, 1a2, and 1b1), and most of the Cyp2 family (Cyp2a4, 2a5, 2a22, 2b9, 2b10, 2b13, 2b19, 2b23, 2c29, 2c37, 2c38, 2c39, 2c40, 2c44, 2c50, 2c54, and 2c55) viii in male and female livers from day -2 to day 45 of age……...……………...97 Figure 5.3. The mRNA ontogenic expression of most of the Cyp2 family (Cyp2c66, 2c67, 2c68, 2c69, 2c70, 2d9, 2d10, 2d11, 2d12, 2d22, 2d26, 2d34, 2d40, 2e1, 2f2, 2g1, 2j5, 2j6, 2j7, and 2j8) in male and female livers from day -2 to day 45 of age……………………………………………...…...100
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  • 1 Mucosal Effects of Tenofovir 1% Gel 1 Florian Hladik1,2,5*, Adam

    1 Mucosal Effects of Tenofovir 1% Gel 1 Florian Hladik1,2,5*, Adam

    1 Mucosal effects of tenofovir 1% gel 2 Florian Hladik1,2,5*, Adam Burgener8,9, Lamar Ballweber5, Raphael Gottardo4,5,6, Lucia Vojtech1, 3 Slim Fourati7, James Y. Dai4,6, Mark J. Cameron7, Johanna Strobl5, Sean M. Hughes1, Craig 4 Hoesley10, Philip Andrew12, Sherri Johnson12, Jeanna Piper13, David R. Friend14, T. Blake Ball8,9, 5 Ross D. Cranston11,16, Kenneth H. Mayer15, M. Juliana McElrath2,3,5 & Ian McGowan11,16 6 Departments of 1Obstetrics and Gynecology, 2Medicine, 3Global Health, 4Biostatistics, University 7 of Washington, Seattle, USA; 5Vaccine and Infectious Disease Division, 6Public Health Sciences 8 Division, Fred Hutchinson Cancer Research Center, Seattle, USA; 7Vaccine and Gene Therapy 9 Institute-Florida, Port St. Lucie, USA; 8Department of Medical Microbiology, University of 10 Manitoba, Winnipeg, Canada; 9National HIV and Retrovirology Laboratories, Public Health 11 Agency of Canada; 10University of Alabama, Birmingham, USA; 11University of Pittsburgh 12 School of Medicine, Pittsburgh, USA; 12FHI 360, Durham, USA; 13Division of AIDS, NIAID, NIH, 13 Bethesda, USA; 14CONRAD, Eastern Virginia Medical School, Arlington, USA; 15Fenway Health, 14 Beth Israel Deaconess Hospital and Harvard Medical School, Boston, USA; 16Microbicide Trials 15 Network, Magee-Women’s Research Institute, Pittsburgh, USA. 16 Adam Burgener and Lamar Ballweber contributed equally to this work. 17 *Corresponding author E-mail: [email protected] 18 Address reprint requests to Florian Hladik at [email protected] or Ian McGowan at 19 [email protected]. 20 Abstract: 150 words. Main text (without Methods): 2,603 words. Methods: 3,953 words 1 21 ABSTRACT 22 Tenofovir gel is being evaluated for vaginal and rectal pre-exposure prophylaxis against HIV 23 transmission.