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64 Publications

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    Tjian Lab
    08/01/10 | Unexpected roles for core promoter recognition factors in cell-type-specific transcription and gene regulation.
    Goodrich JA, Tjian R
    Nature Reviews. Genetics. 2010 Aug;11:549-58. doi: 10.1073/pnas.1100640108

    The eukaryotic core promoter recognition complex was generally thought to play an essential but passive role in the regulation of gene expression. However, recent evidence now indicates that core promoter recognition complexes together with ’non-prototypical’ subunits may have a vital regulatory function in driving cell-specific programmes of transcription during development. Furthermore, new roles for components of these complexes have been identified beyond development; for example, in mediating interactions with chromatin and in maintaining active gene expression across cell divisions.

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    Tjian Lab
    12/25/09 | Shifting players and paradigms in cell-specific transcription.
    D’Alessio JA, Wright KJ, Tjian R
    Molecular Cell. 2009 Dec 25;36(6):924-31. doi: 10.1073/pnas.1100640108

    Historically, developmental-stage- and tissue-specific patterns of gene expression were assumed to be determined primarily by DNA regulatory sequences and their associated activators, while the general transcription machinery including core promoter recognition complexes, coactivators, and chromatin modifiers was held to be invariant. New evidence suggests that significant changes in these general transcription factors including TFIID, BAF, and Mediator may facilitate global changes in cell-type-specific transcription.

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    Tjian Lab
    07/01/09 | Structures of three distinct activator-TFIID complexes.
    Liu W, Coleman RA, Ma E, Grob P, Yang JL, Zhang Y, Dailey G, Nogales E, Tjian R
    Genes & Development. 2009 Jul 1;23(13):1510-21. doi: 10.1073/pnas.1100640108

    Sequence-specific DNA-binding activators, key regulators of gene expression, stimulate transcription in part by targeting the core promoter recognition TFIID complex and aiding in its recruitment to promoter DNA. Although it has been established that activators can interact with multiple components of TFIID, it is unknown whether common or distinct surfaces within TFIID are targeted by activators and what changes if any in the structure of TFIID may occur upon binding activators. As a first step toward structurally dissecting activator/TFIID interactions, we determined the three-dimensional structures of TFIID bound to three distinct activators (i.e., the tumor suppressor p53 protein, glutamine-rich Sp1 and the oncoprotein c-Jun) and compared their structures as determined by electron microscopy and single-particle reconstruction. By a combination of EM and biochemical mapping analysis, our results uncover distinct contact regions within TFIID bound by each activator. Unlike the coactivator CRSP/Mediator complex that undergoes drastic and global structural changes upon activator binding, instead, a rather confined set of local conserved structural changes were observed when each activator binds holo-TFIID. These results suggest that activator contact may induce unique structural features of TFIID, thus providing nanoscale information on activator-dependent TFIID assembly and transcription initiation.

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    Tjian LabSinger LabTranscription Imaging
    02/03/09 | Imaging transcription in living cells.
    Darzacq X, Yao J, Larson DR, Causse SZ, Bosanac L, de Turris V, Ruda VM, Lionnet T, Zenklusen D, Guglielmi B, Tjian R, Singer RH
    Annual Review of Biophysics. 2009 Feb 3;38:173-96. doi: 10.1073/pnas.1100640108

    The advent of new technologies for the imaging of living cells has made it possible to determine the properties of transcription, the kinetics of polymerase movement, the association of transcription factors, and the progression of the polymerase on the gene. We report here the current state of the field and the progress necessary to achieve a more complete understanding of the various steps in transcription. Our Consortium is dedicated to developing and implementing the technology to further this understanding.

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    Tjian Lab
    01/06/09 | Wnt signaling targets ETO coactivation domain of TAF4/TFIID in vivo.
    Wright KJ, Tjian R
    Proceedings of the National Academy of Sciences of the United States of America. 2009 Jan 6;106(1):55-60. doi: 10.1073/pnas.1100640108

    Understanding the diverse activities of the multisubunit core promoter recognition complex TFIID in vivo requires knowledge of how individual subunits contribute to overall functions of this TATA box-binding protein (TBP)/TBP-associated factor (TAF) complex. By generating altered holo-TFIID complexes in Drosophila we identify the ETO domain of TAF4 as a coactivator domain likely targeted by Pygopus, a protein that is required for Wingless-induced transcription of naked cuticle. These results establish a coactivator function of TAF4 and provide a strategy to dissect mechanisms of TFIID function in vivo.

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    Tjian Lab
    10/10/08 | MyoD targets TAF3/TRF3 to activate myogenin transcription.
    Deato MD, Marr MT, Sottero T, Inouye C, Hu P, Tjian R
    Molecular Cell. 2008 Oct 10;32(1):96-105. doi: 10.1073/pnas.1100640108

    Skeletal muscle differentiation requires a cascade of transcriptional events to control the spatial and temporal expression of muscle-specific genes. Until recently, muscle-specific transcription was primarily attributed to prototypic enhancer-binding factors, while the role of core promoter recognition complexes in directing myogenesis remained unknown. Here, we report the development of a purified reconstituted system to analyze the properties of a TAF3/TRF3 complex in directing transcription initiation at the Myogenin promoter. Importantly, this new complex is required to replace the canonical TFIID to recapitulate MyoD-dependent activation of Myogenin. In vitro and cell-based assays identify a domain of TAF3 that mediates coactivator functions targeted by MyoD. Our findings also suggest changes to CRSP/Mediator in terminally differentiated myotubes. This switching of the core promoter recognition complex during myogenesis allows a more balanced division of labor between activators and TAF coactivators, thus providing another strategy to accommodate cell-specific regulation during metazoan development.

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    Tjian Lab
    10/09/08 | The future for Howard Hughes. Interview by Erika Check Hayden.
    Tjian R
    Nature. 2008 Oct 9;455(7214):718. doi: 10.1073/pnas.1100640108
    Tjian Lab
    10/01/08 | Codependent activators direct myoblast-specific MyoD transcription.
    Hu P, Geles KG, Paik J, DePinho RA, Tjian R
    Developmental Cell. 2008 Oct;15(4):534-46. doi: 10.1073/pnas.1100640108

    Although FoxO and Pax proteins represent two important families of transcription factors in determining cell fate, they had not been functionally or physically linked together in mediating regulation of a common target gene during normal cellular transcription programs. Here, we identify MyoD, a key regulator of myogenesis, as a direct target of FoxO3 and Pax3/7 in myoblasts. Our cell-based assays and in vitro studies reveal a tight codependent partnership between FoxO3 and Pax3/7 to coordinately recruit RNA polymerase II and form a preinitiation complex (PIC) to activate MyoD transcription in myoblasts. The role of FoxO3 in regulating muscle differentiation is confirmed in vivo by observed defects in muscle regeneration caused by MyoD downregulation in FoxO3 null mice. These data establish a mutual interdependence and functional link between two families of transcription activators serving as potential signaling sensors and regulators of cell fate commitment in directing tissue specific MyoD transcription.

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    Tjian Lab
    09/01/08 | TBP, Mot1, and NC2 establish a regulatory circuit that controls DPE-dependent versus TATA-dependent transcription.
    Hsu J, Juven-Gershon T, Marr MT, Wright KJ, Tjian R, Kadonaga JT
    Genes & Development. 2008 Sep 1;22(17):2353-8. doi: 10.1073/pnas.1100640108

    The RNA polymerase II core promoter is a structurally and functionally diverse transcriptional module. RNAi depletion and overexpression experiments revealed a genetic circuit that controls the balance of transcription from two core promoter motifs, the TATA box and the downstream core promoter element (DPE). In this circuit, TBP activates TATA-dependent transcription and represses DPE-dependent transcription, whereas Mot1 and NC2 block TBP function and thus repress TATA-dependent transcription and activate DPE-dependent transcription. This regulatory circuit is likely to be one means by which biological networks can transmit transcriptional signals, such as those from DPE-specific and TATA-specific enhancers, via distinct pathways.

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    Tjian Lab
    05/06/08 | ES cell pluripotency and germ-layer formation require the SWI/SNF chromatin remodeling component BAF250a.
    Gao X, Tate P, Hu P, Tjian R, Skarnes WC, Wang Z
    Proceedings of the National Academy of Sciences of the United States of America. 2008 May 6;105(18):6656-61. doi: 10.1073/pnas.1100640108

    ATP-dependent chromatin remodeling complexes are a notable group of epigenetic modifiers that use the energy of ATP hydrolysis to change the structure of chromatin, thereby altering its accessibility to nuclear factors. BAF250a (ARID1a) is a unique and defining subunit of the BAF chromatin remodeling complex with the potential to facilitate chromosome alterations critical during development. Our studies show that ablation of BAF250a in early mouse embryos results in developmental arrest (about embryonic day 6.5) and absence of the mesodermal layer, indicating its critical role in early germ-layer formation. Moreover, BAF250a deficiency compromises ES cell pluripotency, severely inhibits self-renewal, and promotes differentiation into primitive endoderm-like cells under normal feeder-free culture conditions. Interestingly, this phenotype can be partially rescued by the presence of embryonic fibroblast cells. DNA microarray, immunostaining, and RNA analyses revealed that BAF250a-mediated chromatin remodeling contributes to the proper expression of numerous genes involved in ES cell self-renewal, including Sox2, Utf1, and Oct4. Furthermore, the pluripotency defects in BAF250a mutant ES cells appear to be cell lineage-specific. For example, embryoid body-based analyses demonstrated that BAF250a-ablated stem cells are defective in differentiating into fully functional mesoderm-derived cardiomyocytes and adipocytes but are capable of differentiating into ectoderm-derived neurons. Our results suggest that BAF250a is a key component of the gene regulatory machinery in ES cells controlling self-renewal, differentiation, and cell lineage decisions.

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