Title: Molecular mechanisms underlying differentiel transcriptional regulation and function by thyroid hormone receptor isoforms
Directors: Karine GAUTHIER-VANACKER & WENG Jiemin
Discipline: Life science
Status: Developing project
Starting date: 2015/2012. This project was incubated at JoRiss from 2012 to 2015.
Supervision
KARINE GAUTHIER VANACKER
Contact informations:
Karine Gauthier
Functional Genomic of Nuclear Receptor
UMR5242/IGFL
ENS de Lyon
46 allée d’Italie
69364 Lyon cedex 07
France
Tel : +33 472728616
E-mail : Karine.Gauthier [at] ens-lyon.fr
Karine Gauthier studied at the ENS de Lyon and obtained her PhD in the Lab of Jacques Samarut (1996-2000) in this school. During these years she generated several of the knock-out mice currently used in a number of labs to study Thyroid Hormone Receptor (TR) functions. She participated to the early collaborative effort to characterize those mice, for a better understanding of TR roles during early postnatal development.
She then moved for her postdoctoral training (2001-2004) to David Mangelsdorf Lab at UTSW Medical Center in Dallas (TX USA) where she was an HHMI research associate. She kept on studying there nuclear receptors function using knock-out mouse models. She had special interest in finding new ligands for PXR and in studying the role of LXR in fat metabolism and macrophage functions.
She came back in France in 2004 as a permanent investigator (CR CNRS) in Jacques Samarut lab, where she is now directing a small group of people. She studies the role of Thyroid Hormones and their receptors TR in the control of lipid and glucose metabolism in peripheral tissues and their involvement in metabolic diseases development.
She is a member of the NSFA for the last three years, reviews papers for ATVB, plos one or molecular endocrinology regularly and has been selected or invited to give talks in many national and international congresses in the past years.
WENG JIEMIN
Jiemin WENG, Ph.D.
Professor and Associate Director
The Institute of Biomedical Sciences and School of Life Sciences
East China Normal University
500 Dongchuan Road
Shanghai 200241
P. R. China
Education:
1980-1984 B.S. in Microbiology, Wuhan University (Wuhan, China)
1984-1987 M.S. in Cell Biology, Shanghai Institute of Cell Biology,
Academy of Science
1989-1994 Ph.D. in Microbiology and Molecular Genetics, University of
Vermont , USA
Professional Experience:
1987-1989 Research Assistant, Shanghai Institute of Organic Chemistry,
Shanghai, China. 1994-1997 Postdoctoral Fellow at Lab. of
Molecular Embryology, NICHD/NIH.
1997-2003 Assistant Professor, Department of Molecular and Cellular
Biology, Baylor College of Medicine, USA
2003-2007 Associate Professor, Department of Molecular and Cellular
Biology, Baylor College of Medicine, USA
2007-present Professor and Associate Director, The Institute of Biomedical
Sciences, East China Normal University
Publications:
1. Chen, H.B., WENG, J., Jiang, K. and Bao, J.S. 1990. A new method for
the synthesis of a structural gene. Nucleic Acids Res. 18, 871-878.
2. WENG, J., Liu, F., and Bateman, E. 1992. Cloning and expression of the
Acathamoeba castellanii gene encoding transcription factor TFIID. Gene 117, 91-97.
3. WENG, J., Liu, F., and Bateman. E. 1992. Isolation of genomic DNA encoding transcription factor TFIID from Acanthamoeba castellanii:: characterization of the promoter. Nucleic Acids Res. 20, 4817-4826.
4. Radebaugh, C.A., Matthews, J. L., Geiss, G. K., Liu, F., WENG, J., Bateman, E., Camier, S., Sentenac, A. and Paule, M. R. 1994. TATA-box binding protein (TBP) is a constituent of the polymerase I-specific transcription initiation factor TIF-IB (SL1) bound to the rRNA promoter and shows differential sensitivity to TBP-directed reagents in polymerase I, II, and III transcription factors. Mol. Cell. Biol. 14, 597-605.
5. WENG, J. and Bateman, E. 1994. TBP-DNA interactions in the minor groove discriminate between A:T and T:A base pairs. Nucleic Acids Res. 22, 1890-1896.
6. WENG, J. and Bateman, E. 1994. Cloning of the cDNA encoding an Acanthamoeba castellanii PDI-like protein. Gene. 150, 175-179.
7. Ranjan, M., WENG, J. and Shi, Y-B. 1994. Transcriptional repression of Xenopus TRBA gene is mediated by a thyroid hormone response element located near the start site. J. Biol. Chem. 269, 24699-24705.
8. WENG, J., Shi, Y-B. and Wolffe, A.P. 1995. A role of nucleosome assembly in the transcriptional regulation of Xenopus TRBA gene by thyroid hormone receptor. Gene & Development. 9, 2696-2711.
9. WENG, J. and Shi, Y-B. 1995. Coordinated regulation of and transcriptional activation by Xenopus thyroid hormone and retinoid X receptors. J. Biol. Chem. 270, 18479-18483.
10. Waibao Huang, WENG, J. and Bateman, E. 1996. TATA elements direct bi-directional transcription by RNA polymerase II and III. Nucleic Acid Res. 24, 1158-1163..
11.Shi, Y.-B., M.A. Stolow, M. Puzianowska-Kuznicka, and WENG, J. 1996. Les genes de la metamorphose. La Recherche 286: 58-64.
12.Shi, Y.-B.,WENG, J., M. Puzianowska-Kuznicka and M.A. Stolow. 1996. Tadpole Competence and Tissue-Specific Temporal Regulation of Amphibian Metamorphosis: Roles of Thyroid Hormone and Its Receptors. Bioessays 18(5): 391-399.
13. Puzianowska-Kuznicki, M., WENG, J. and Shi, Y-B. 1996. Functional characterization of a mutant thyroid hormone receptor in Xenopus Laevis. J. Biol. Chem 270, 33394-33403
14. WENG, J., Shi, Y-B., and Wolffe, A.P. 1997. Determinants of chromatin disruption and transcriptional regulation instigated by the thyroid hormone receptor: hormone-regulated chromatin disruption is not sufficient for transcriptional activation. EMBO J. 16(11): 3158-3171.
15. WENG, J., Li, Q., Levi, B-Z., Shi, Y-B., and Wolffe, A.P. 1997. Structural and functional features of a specific nucleosome containing a recognition element for the thyroid hormone receptor. EMBO J. 16(23): 7130-7145.
16. WENG, J., Patterton, D., Imhof, A., Guschin, D., Shi, Y-B., and Wolffe AP. 1998. Distinct requirements for chromatin assembly in transcriptional repression by thyroid hormone receptor and histone deacetylase. EMBO J. 17(2): 520-534.
17. Minucci, S., WENG, J., Blanco, J.C., Shi, Y-B., Wolffe, A.P., and Ozato K. 1998. Retinoid receptor-induced alteration of the chromatin assembled on a ligand-responsive promoter in Xenopus oocytes. Mol Endocrinol. 12(3):315-324.
18. Wolffe, A.P., WENG, J., and Pruss, D. 1997. Activators and repressors: making use of chromatin to regulate transcription. Genes Cells 2(5):291-302.
19. Wolffe, A.P., WENG, J., Li, Q., Levi, B.Z., and Shi Y-B. 1997. Three steps in the regulation of transcription by the thyroid hormone receptor: establishment of a repressive chromatin structure, disruption of chromatin and transcriptional activation. Biochem Soc Trans 25(2):612-615.
20. WENG J., Liang, V.C., Sachs, L.M., and Shi, Y.B. 1998. Transcription from the thyroid hormone-dependent promoter of the Xenopus laevis thyroid hormone receptor betaA gene requires a novel upstream element and the initiator, but not a TATA Box. J Biol Chem 273:14186-93.
21. Xue, Y., WENG, J., Moreno, G.T., Young, M.A., Cote, J., and Wang, W. 1998. NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Molecular Cell 2: 851-861.
22. Lanz, R. B., Mckenna, N.J., Onate, S.A., Albrecht, U., WENG, J., Tsai, S.Y., Tsai, M-J. and O’Malley B.W. 1999. A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex. Cell 97: 17-27.
23. Liu, Z., WENG, J., Tsai, S.Y., Tsai, M-J and O’Malley B.W. 1999. Steroid receptor coactivator-1 (SRC-1) enhances ligand-dependent and receptor-dependent cell free transcription of chromatin. PNAS 96: 9485-9490.
24. Li, J., O’Malley B.W and WENG J. 2000. p300 requires its HAT activity and SRC-1 interaction motif to facilitate TR activation in chromatin. Mol. Cell. Biol. 20: 2031-2042.
25. Li, J,. Wang, J; Wang, J; Nawaz, Z; Liu, J., Jun, Q., and WENG, J. 2000. Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3. EMBO J. 19(16): 4342-4350.
26. Wang, H., Huang, Z., Xia, L., Feng, Q., Erdjument-Bromage, H., Strahl, BD., Briggs, SD., Allis, CD., WENG, J., Tempst, p and Zhang, Y. 2001. Methylation of Histone H4 at Arginine 3 Facilitates Transcriptional Activation by Nuclear Hormone Receptor. Science 293: 853-857.
27. Liu, Z., WENG, J., Tsai, S.Y., Tsai, M-J and O’Malley B.W. 2001. Sequential recruitment of steroid receptor coactivator-1 (SRC-1) and p300 enhances progesterone receptor-dependent initiation and reinitiation of transcription from chromatin. PNAS 98: 12426-12431.
28. Huang, Z., Li, J. and WENG, J. 2002. Androgen receptor possesses an intrinsic-hormone-independent trans-activation activity. Mol Endocrinol. 16: 924-937.
29. Liu Z, Auboeuf D, WENG J, Chen JD, Tsai SY, Tsai MJ, O'Malley BW. 2002. Coactivator/corepressor ratios modulate PR-mediated transcription by the selective receptor modulator RU486. Proc Natl Acad Sci U S A. 99(12):7940-4.
30. Li, J; Lin, Q; Wade, P., Wang, W and WENG, J. 2002. Specific targeting and constitutive association of histone deacetylase complexes during transcriptional repression. Genes & Development 16: 687-692.
31. Wu, R.C., Qin, J., Hashimoto, Y., WENG, J., Xu, J., Tsai, S.Y., Tsai, M.J, and O'Malley B.W. 2002. Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator Activity by IkappaB Kinase. Mol Cell Biol 22(10):3549-61.
32. Li, J., Lin, Q., Yoon, H-G., Huang, Z., Strahl, B.D., Allis, C.D., and WENG, J. 2002. The involvement of multiple histone methylation in transcriptional regulation by thyroid hormone receptor. Mol Cell Biol 22 (16): 5688-5697.
33. Suh YA, Lee HY, Virmani A, WENG J, Mann KK, Miller WH Jr, Gazdar A, Kurie JM. 2002. Loss of retinoic acid receptor beta gene expression is linked to aberrant histone H3 acetylation in lung cancer cell lines. Cancer Res. 2002 Jul 15;62(14):3945-9.
34. Kraus WL and WENG J. 2002. Nuclear Receptor-Dependent transcription from Chromatin: Its All About Enzymes? Eur J Biochem 269:1-9.
35. WENG J. 2002. Transcriptional regulation by thyroid hormone receptor in chromatin. Thyroid hormone receptors: Methods in Molecular Biology edited by Aria Baniahmad, p177-194.
36. Osborne CK, Bardou V, Hopp TA, Chamness GC, Hilsenbeck SG, Fuqua SA, WENG J, Schiff R, Allred DC and Clark GM. 2003. Overexpression of the Estrogen Receptor Coactivator AIB1 (SRC3) and the HER-2/neu Oncogene are Both Necessary for the Tamoxifen-Resistance in ER-Positive Primary Breast Cancers. J Natl Cancer Insti. 95(5):353-61.
37. Cheskis BJ, McKenna NJ, WENG CW, WENG J, Komm B, Lyttle CR, O'Malley BW. 2003. Hierarchical affinities and a bipartite interaction model for estrogen receptor isoforms and full length steroid receptor coactivator (SRC/p160) family members. J Biol Chem. 278(15):13271-7.
38. Yoon HG, Chan DW, Huang ZQ, Li J, Fondell JD, Qin J and WENG J. 2003. Purification and Functional Characterization of the Human N-CoR Complex: the Roles of HDAC3 and two WD-40 Repeat Subunits TBL1 and TBLR1. EMBO J 22(6):1336-1346.
39. Lee KC#, Li J#, Cole PA, WENG J* and Kraus L*. 2003. Transcriptional activation by thyroid hormone receptor involves chromatin remodeling, histone acetylation, and cooperative stimulation by p300 and SRC coactivators. Mol Endocrinol. 17(5):908-22. (#equal contribution and co-corresponding authors.)
40. Huang ZQ, Li J, Sachs LM, Cole PA and WENG J. 2003. A Role for Cofactor-Cofactor and Cofactor-Histone Interaction in Targeting of CBP/p300, SWI/SNF and Mediator for transcription. EMBO J 22(9):2146-2155.
41. Li X, WENG J, Tsai S, Tsai M and O’malley BW. 2003. Progesterone and Glucocorticoid Receptors Recruite distinct Coactivator Complexes and Promote Distinct Patterns of Local Chromatin Modification. Mol Cell Biol. 23(11):3763-73.
42. Yoon HG, Chan DW, Reynolds AB, Qin J and WENG J. 2003. Kaiso targets the N-CoR corepressor complex for DNA methylation mediated repression. Molecular Cell 12, 723-734.
43. Xin H, Yoon HG, Singh PB, WENG J, Qin J. 2004. Components of a pathway maintaining histone modification and HP1 binding at the pericentric heterochromatin in mammalian cells. J Biol Chem. 279(10):9539-46.
44. Paul R. Thompson, Dongxia Wang, Ling Wang, Marcella Fulco, Natalia Pediconi, DianZheng Zhang, Woojin An, Qingyuan Ge, Robert G. Roeder, WENG J, Massimo Levrero, Vittorio Sartorelli, Robert J. Cotter, Philip A. Cole. 2004. Regulation of the p300 HAT Domain via a Novel Activation Loop. Nature Structural and Molecular Biology. 11(4): 308-15.
45. Wu RC, Qin J, Yi P, WENG J, Tsai SY, Tsai MJ, O'Malley BW. 2004. Selective Phosphorylations of the SRC-3/AIB1 Coactivator Integrate Genomic Reponses to Multiple Cellular Signaling Pathways. Molecular Cell.15(6):937-49.
46. Stewart MD and WENG J. 2004. Curr. Opin. Endocrinol. Diabetes 11: 218-225.
47. Yoon HG, Choi Y, Cole PA and WENG J. 2005 Reading and Function of a histone code involved in targeting corepressor complexes for repression. Mol Cell Biol;25(1):324-335.
48. Stewart MD, Li J and WENG J. 2005 Relationship between H3 lysine 9 methylation, transcription repression and heterochromatin protein 1 recruitment. Mol Cell Biol;25(7):2525-38.
49. Zhang D, Yoon HG and WENG J. 2005. JMJD2A is a novel N-CoR-interacting protein and is involved in repression of the human transcription factor achaete scute-like homologue 2 (ASCL2/Hash2). Mol Cell Biol;25(15):6404-14.
50. Burd CJ, Petre CE, Morey LM, Wang Y, Revelo MP, Haiman CA, Lu S, Fenoglio-Preiser CM, Li J, Knudsen ES, WENG J and Knudsen KE. 2006 Cyclin D1b variant influences prostate cancer growth through aberrant androgen receptor regulation. Proc Natl Acad Sci U S A; 103:2190-5.
51. Yi P, Wu RC, Sandquist J, WENG J, Tsai SY, Tsai MJ, Means AR, O'Malley BW. 2005. Peptidyl-prolyl isomerase 1 (Pin1) serves as a coactivator of steroid receptor by regulating the activity of phosphorylated steroid receptor coactivator 3 (SRC-3/AIB1). Mol Cell Biol.25(21):9687-99.
52. Yoon, H. G., and WENG J. 2006. The corepressors silencing mediator of retinoid and thyroid hormone receptor and nuclear receptor corepressor are involved in agonist- and antagonist-regulated transcription by androgen receptor. Mol Endocrinol 20:1048-60.
53. Jiang S, Meyer R, Kang K, Osborne CK, WENG J, Oesterreich S. 2006. Scaffold attachment factor SAFB1 suppresses estrogen receptor alpha-mediated transcription in part via interaction with nuclear receptor corepressor. Mol Endocrinol. 20(2):311-20.
54. Stewart D, Tomita A, Shi YB, WENG J. 2006. Chromatin immunoprecipitation for studying transcriptional regulation in Xenopus oocytes and tadpoles. Methods Mol Biol. 322:165-81. Review.
55. Klose, R. Yamane JK, Bae Y, Zhang D, Erdjument-Bromage H, Tempst P, WENG J and Zhang Y. 2006. The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36. Nature 442:312-316.
56. Li, J., Fu J, Toumazou C, Yoon HG, and WENG J. 2006. A role of the amino-terminal (N) and carboxyl-terminal (C) interaction in binding of androgen receptor to chromatin. Mol Endocrinol 20:776-85.
57. Qiu J, WENG J, Tweardy DJ, Dong S. Decreased intranuclear mobility of acute myeloid leukemia 1-containing fusion proteins is accompanied by reduced mobility and compartmentalization of core binding factor beta. Oncogene. 2006 Jun 29;25(28):3982-93.
58. Yamane, K., Toumazou C, Tsukada YI, Erdjument-Bromage H, Tempst P, WENG J and Zhang Y. 2006. JHDM2A, a JmjC-Containing H3K9 Demethylase, Facilitates Transcription Activation by Androgen Receptor. Cell 125:483-95.
59. Feng, Q., P. Yi, J. WENG, and W. O'Malley B. 2006. Signaling within a coactivator complex: Methylation of SRC-3/AIB1 is a molecular switch for complex disassembly. Mol Cell Biol. 26:7846-57.
60. Stewart, M. D., J. Sommerville, and J. WENG. 2006. Dynamic regulation of histone modifications in Xenopus oocytes through histone exchange. Mol Cell Biol 26:6890-901.
61. Grégoire, S., Lin Xiao, Jianyun Nie, Xiaohong Zhang, Minghong Xu, Jiarong Li, J. WENG, Edward Seto, and Xiang-Jiao Yang. 2007. Histone deacetylase 3 interacts with and deacetylates MEF2 transcription factors. Mol Cell Biol 27:1280-95.
62. Fu, J., Yoon, HG., Qin, J. and WENG J. Regulation of P-TEFb Elongation Complex Activity by CDK9 Acetylation. Mol Cell Biol. 2007. 27(13):4641-51
63. Karagianni P and WENG J. 2007. HDAC3: taking the SMRT-N-CoRrect road to repression. Oncogene 26(37):5439-49.
64. Zhang D, Cho E, and WENG J. 2007. A critical role for the co-repressor N-CoR in erythroid differentiation and heme synthesis. Cell Res. 17:804-814.
65. Lee YH, Hong SW, Jun W, Cho HY, Kim HC, Jung MG, WENG J, Kim HI, Kim CH, Yoon HG. Anti-histone acetyltransferase activity from allspice extracts inhibits androgen receptor-dependent prostate cancer cell growth. Biosci Biotechnol Biochem. 2007 71(11):2712-9.
66. Karagianni P, Amazit L, Qin J, WENG J. 2008. ICBP90, a novel methyl K9 H3 binding protein linking protein ubiquitination with heterochromatin formation. Mol Cell Biol 28(2):705-17
67. Ishii S, Kurasawa Y, WENG J, Yu-Lee LY. 2008. Histone deacetylase 3 localizes to the mitotic spindle and is required for kinetochore-microtubule attachment. PNAS 105(11):4179-84.
68. Liang J, Wan M, Zhang Y, Gu P, Xin H, Jung SY, Qin J, WENG J, Cooney AJ, Liu D, and Songyang Z. 2008. Nanog and Oct4 associate with unique transcriptional repression complexes in embryonic stem cells. Nature Cell Biology.10(6):731-739.
69．Fu j, Jiang J, Li J, Wang S, Shi G, Feng Q, White E, Qin J and WENG J. 2009. The deleted in brest cancer 1 (DBC-1): A novel AR coactivator that promotes AR DNA binding activity. J Biol Chem. 284(11):6832-40.
70．Chan D, Wang Y, Wu M, WENG J, Qin J and Zhao Y. 2009. Unbiased proteomic screen for binding proteins to modified lysines on histone H3. Proteomics 9(9):2343-54.
71. Yang Z, Jiang J, Stewart DM, Qi S, Yamane K, Li J, Zhang Y, WENG J. 2010. AOF1 is a histone H3K4 demethylase possessing demethylase activity-independent repression function. Cell Res. 20(3):276-87
72. Qiu J, Shi G, Jia Y, Li J, Wu M, Li J, Dong S and WENG J. 2010. The X-linked mental retardation gene PHF8 is a histone demethylase involved in neuronal differentiation. Cell Res. 20(8):908-18.
73. Fu J, Qin L, He T, Qin J, Hong J, WENG J, Liao L, Xu J. 2011. The TWIST/Mi2/NuRD protein complex and its essential role in cancer metastasis. Cell Res. 21(2):275-89.
74. Shen J, Zhang S, Li Y, Zhang W, Chen J, Zhang M, Wang T, Jiang L, Zou X, WENG J, Li X, Cui Y, Wang C. 2011. p14(ARF) inhibits the functions of adenovirus E1A oncoprotein. Biochem J. 434(2):275-85.
75. Zhang J, Gao Q, Li P, Liu X, Jia Y, Wu W, Li J, Dong S, Koseki H, WENG J. 2011. S phase-dependent interaction with DNMT1 dictates the role of UHRF1 but not UHRF2 in DNA methylation maintenance. Cell Res. 21(12):1723-39.
76. Li, J., Chu, M., Wang, S., Chan, D., Qi, S., Wu, M., Zhou, Z., Li, J., Nishi, E., Qin, J. WENG J. (2012). Identification and Characteriation of Nardilysin as a Novel Dimethyl H3K4 Binding Protein Involved in Transcriptional Regulation. J Biol Chem. 【EPUB】
77. Wu J, Cui N, Wang R, Li J and WENG J. A role for CARM1-mediated histone H3 methylation in protecting histone acetylation by releasing corepressors from chromatin. PLoS One . In Press.
78. Zhang H, Ma Y, Gu J, Liao B, Li J, WENG J, Jin Y. Reprogramming of somatic cells via TAT-mediated protein transduction of recombinant factors. Biomaterials. In Press.
Summary
Thyroid hormone (T3) exerts a pleiotropic action on development and homeostasis. T3 acts on gene transcription by binding to the thyroid hormone receptors (TRs), including the TRα and TRβ isoforms. The transcriptional activity of TR is regulated by T3 binding which redefines the protein-protein interactions occurring at the receptor surface, in particular with cofactors necessary for their function.
Genome wide studies have recently highlighted that the T3 target gene repertories are very divergent in different tissues. This likely reflects specific expression and/or activity of the various TR isoforms in each given system. Moreover our recent results show that for some genes, in white adipose tissue (WAT), the regulation by T3 is TRβ selective even though TRα is also expressed. The questions we propose to tackle, using WAT as our model, is the following: to what extent are isoform selective regulation and the molecular mechanism responsible for this selectivity?
First we will try to identify new isoform-selective target genes in this tissue using mice in which either TRα or TRβ function has been abrogated. WAT T3 response will be determined by RNA massive sequencing. Comparison of the different genotypes will assess how many of the T3 targets are actually regulated in a TR isoform selective manner.
We will also test whether this isoform selectivity could rely on the different isoforms binding to- and being activated by- specific and different co-factors. To this end tagged TRα and TRβ proteins will be produced to test their ability to interact with a wide range of cofactors in presence or absence of T3 using pull down assay. If conclusive this in vitro study will be undertaken further in WAT.
This project is only possible thanks to the complementary expertise of the two labs in mouse genetics (ENS) and biochemistry (ECNU).