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64 Publications

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    Tjian Lab
    03/01/06 | Cryo-electron microscopy studies of human TFIID: conformational breathing in the integration of gene regulatory cues.
    Grob P, Cruse MJ, Inouye C, Peris M, Penczek PA, Tjian R, Nogales E
    Structure. 2006 Mar;14(3):511-20. doi: 10.1073/pnas.1100640108

    The multisubunit transcription factor TFIID is essential for directing eukaryotic promoter recognition and mediating interactions with activators/cofactors during assembly of the preinitiation complex. Despite its central role in transcription initiation and regulation, structural knowledge of the TFIID complex has so far been largely limited to electron microscopy studies of negatively stained samples. Here, we present a cryo-electron microscopy 3D reconstruction of the large endogenous human TFIID complex. The improved cryopreservation has allowed for a more detailed definition of the structural elements in the complex and for the detection, by an extensive statistical analysis of the data, of a conformational opening and closing of the cavity central to the TFIID architecture. We propose that these density rearrangements in the structure are a likely reflection of the plasticity of the interactions between TFIID and its many partner proteins.

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    Tjian Lab
    03/01/06 | Nutrient availability and growth: regulation of insulin signaling by dFOXO/FOXO1.
    Puig O, Tjian R
    Cell Cycle. 2006 Mar;5(5):503-5. doi: 10.1073/pnas.1100640108

    Organisms adjust their rate of growth depending on the availability of nutrients. Thus, when environmental conditions limit nutrients, growth is slowed and is only restored after food again becomes abundant. Many aspects of the molecular mechanisms that govern this complex control system remain unknown. However, it has been shown that the insulin/IGF-1 (insulin-like growth factor 1) receptor pathway, together with the FOXO family of transcription factors, play an important role in this process. Recent studies with the fruit fly Drosophila melanogaster have provided new insights into the regulatory circuitry that controls both growth and gene expression in response to nutrient availability.

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    Tjian Lab
    02/21/06 | Cell-type-selective induction of c-jun by TAF4b directs ovarian-specific transcription networks.
    Geles KG, Freiman RN, Liu W, Zheng S, Voronina E, Tjian R
    Proceedings of the National Academy of Sciences of the United States of America. 2006 Feb 21;103(8):2594-9. doi: 10.1073/pnas.1100640108

    Cell-type-selective expression of the TFIID subunit TAF(II)105 (renamed TAF4b) in the ovary is essential for proper follicle development. Although a multitude of signaling pathways required for folliculogenesis have been identified, downstream transcriptional integrators of these signals remain largely unknown. Here, we show that TAF4b controls the granulosa-cell-specific expression of the proto-oncogene c-jun, and together they regulate transcription of ovary-selective promoters. Instead of using cell-type-specific activators, our findings suggest that the coactivator TAF4b regulates the expression of tissue-specific genes, at least in part, through the cell-type-specific induction of c-jun, a ubiquitous activator. Importantly, the loss of TAF4b in ovarian granulosa cells disrupts cellular morphologies and interactions during follicle growth that likely contribute to the infertility observed in TAF4b-null female mice. These data highlight a mechanism for potentiating tissue-selective functions of the basal transcription machinery and reveal intricate networks of gene expression that orchestrate ovarian-specific functions and cell morphology.

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    Tjian Lab
    12/29/05 | In vitro analysis of huntingtin-mediated transcriptional repression reveals multiple transcription factor targets.
    Zhai W, Jeong H, Cui L, Krainc D, Tjian R
    Cell. 2005 Dec 29;123(7):1241-53. doi: 10.1073/pnas.1100640108

    Transcriptional dysregulation has emerged as a potentially important pathogenic mechanism in Huntington’s disease, a neurodegenerative disorder associated with polyglutamine expansion in the huntingtin (htt) protein. Here, we report the development of a biochemically defined in vitro transcription assay that is responsive to mutant htt. We demonstrate that both gene-specific activator protein Sp1 and selective components of the core transcription apparatus, including TFIID and TFIIF, are direct targets inhibited by mutant htt in a polyglutamine-dependent manner. The RAP30 subunit of TFIIF specifically interacts with mutant htt both in vitro and in vivo to interfere with formation of the RAP30-RAP74 native complex. Importantly, overexpression of RAP30 in cultured primary striatal cells protects neurons from mutant htt-induced cellular toxicity and alleviates the transcriptional inhibition of the dopamine D2 receptor gene by mutant htt. Our results suggest a mutant htt-directed repression mechanism involving multiple specific components of the basal transcription apparatus.

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    Tjian Lab
    10/15/05 | Transcriptional feedback control of insulin receptor by dFOXO/FOXO1.
    Puig O, Tjian R
    Genes & Development. 2005 Oct 15;19(20):2435-46. doi: 10.1073/pnas.1100640108

    The insulin signaling pathway, which is conserved in evolution from flies to humans, evolved to allow a fast response to changes in nutrient availability while keeping glucose concentration constant in serum. Here we show that, both in Drosophila and mammals, insulin receptor (InR) represses its own synthesis by a feedback mechanism directed by the transcription factor dFOXO/FOXO1. In Drosophila, dFOXO is responsible for activating transcription of dInR, and nutritional conditions can modulate this effect. Starvation up-regulates mRNA of dInR in wild-type but not dFOXO-deficient flies. Importantly, FOXO1 acts in mammalian cells like its Drosophila counterpart, up-regulating the InR mRNA level upon fasting. Mammalian cells up-regulate the InR mRNA in the absence of serum, conditions that induce the dephosphorylation and activation of FOXO1. Interestingly, insulin is able to reverse this effect. Therefore, dFOXO/FOXO1 acts as an insulin sensor to activate insulin signaling, allowing a fast response to the hormone after each meal. Our results reveal a key feedback control mechanism for dFOXO/FOXO1 in regulating metabolism and insulin signaling.

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    Tjian Lab
    04/01/05 | Maintenance of spermatogenesis requires TAF4b, a gonad-specific subunit of TFIID.
    Falender AE, Freiman RN, Geles KG, Lo KC, Hwang K, Lamb DJ, Morris PL, Tjian R, Richards JS
    Genes & Development. 2005 Apr 1;19(7):794-803. doi: 10.1073/pnas.1100640108

    The establishment and maintenance of spermatogenesis in mammals requires specialized networks of gene expression programs in the testis. The gonad-specific TAF4b component of TFIID (formerly TAF(II)105) is a transcriptional regulator enriched in the mouse testis. Herein we show that TAF4b is required for maintenance of spermatogenesis in the mouse. While young Taf4b-null males are initially fertile, Taf4b-null males become infertile by 3 mo of age and eventually exhibit seminiferous tubules devoid of germ cells. At birth, testes of Taf4b-null males appear histologically normal; however, at post-natal day 3 gonocyte proliferation is impaired and expression of spermatogonial stem cell markers c-Ret, Plzf, and Stra8 is reduced. Together, these data indicate that TAF4b is required for the precise expression of gene products essential for germ cell proliferation and suggest that TAF4b may be required for the regulation of spermatogonial stem cell specification and proliferation that is obligatory for normal spermatogenic maintenance in the adult.

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    Tjian Lab
    02/01/05 | Structural studies of the human PBAF chromatin-remodeling complex.
    Leschziner AE, Lemon B, Tjian R, Nogales E
    Structure. 2005 Feb;13(2):267-75. doi: 10.1073/pnas.1100640108

    ATP-dependent chromatin remodeling is one of the central processes responsible for imparting fluidity to chromatin and thus regulating DNA transactions. Although knowledge on this process is accumulating rapidly, the basic mechanism (or mechanisms) by which the remodeling complexes alter the structure of a nucleosome is not yet understood. Structural information on these macromolecular machines should aid in interpreting the biochemical and genetic data; to this end, we have determined the structure of the human PBAF ATP-dependent chromatin-remodeling complex preserved in negative stain by electron microscopy and have mapped the nucleosome binding site using two-dimensional (2D) image analysis. PBAF has an overall C-shaped architecture–with a larger density to which two smaller knobs are attached–surrounding a central cavity; one of these knobs appears to be flexible and occupies different positions in each of the structures determined. The 2D analysis of PBAF:nucleosome complexes indicates that the nucleosome binds in the central cavity.

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    Tjian Lab
    12/15/04 | Polybromo protein BAF180 functions in mammalian cardiac chamber maturation.
    Wang Z, Zhai W, Richardson JA, Olson EN, Meneses JJ, Firpo MT, Kang C, Skarnes WC, Tjian R
    Genes & Development. 2004 Dec 15;18(24):3106-16. doi: 10.1073/pnas.1100640108

    BAF and PBAF are two related mammalian chromatin remodeling complexes essential for gene expression and development. PBAF, but not BAF, is able to potentiate transcriptional activation in vitro mediated by nuclear receptors, such as RXRalpha, VDR, and PPARgamma. Here we show that the ablation of PBAF-specific subunit BAF180 in mouse embryos results in severe hypoplastic ventricle development and trophoblast placental defects, similar to those found in mice lacking RXRalpha and PPARgamma. Embryonic aggregation analyses reveal that in contrast to PPARgamma-deficient mice, the heart defects are likely a direct result of BAF180 ablation, rather than an indirect consequence of trophoblast placental defects. We identified potential target genes for BAF180 in heart development, such as S100A13 as well as retinoic acid (RA)-induced targets RARbeta2 and CRABPII. Importantly, BAF180 is recruited to the promoter of these target genes and BAF180 deficiency affects the RA response for CRABPII and RARbeta2. These studies reveal unique functions of PBAF in cardiac chamber maturation.

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    Tjian Lab
    07/01/04 | Distinct conformational states of nuclear receptor-bound CRSP-Med complexes.
    Taatjes DJ, Schneider-Poetsch T, Tjian R
    Nature Structural & Molecular Biology. 2004 Jul;11(7):664-71. doi: 10.1073/pnas.1100640108

    The human CRSP-Med coactivator complex is targeted by a diverse array of sequence-specific regulatory proteins. Using EM and single-particle reconstruction techniques, we recently completed a structural analysis of CRSP-Med bound to VP16 and SREBP-1a. Notably, these activators induced distinct conformational states upon binding the coactivator. Ostensibly, these different conformational states result from VP16 and SREBP-1a targeting distinct subunits in the CRSP-Med complex. To test this, we conducted a structural analysis of CRSP-Med bound to either thyroid hormone receptor (TR) or vitamin D receptor (VDR), both of which interact with the same subunit (Med220) of CRSP-Med. Structural comparison of TR- and VDR-bound complexes (at a resolution of 29 A) indeed reveals a shared conformational feature that is distinct from other known CRSP- Med structures. Importantly, this nuclear receptor-induced structural shift seems largely dependent on the movement of Med220 within the complex.

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    Tjian Lab
    06/04/04 | Structure and function of CRSP/Med2; a promoter-selective transcriptional coactivator complex.
    Taatjes DJ, Tjian R
    Molecular Cell. 2004 Jun 4;14(5):675-83. doi: 10.1073/pnas.1100640108

    The multi-subunit, human CRSP coactivator-also known as Mediator (Med)-regulates transcription by mediating signals between enhancer-bound factors (activators) and the core transcriptional machinery. Interestingly, different activators are known to bind distinct subunits within the CRSP/Med complex. We have isolated a stable, endogenous CRSP/Med complex (CRSP/Med2) that specifically lacks both the Med220 and the Med70 subunits. The three-dimensional structure of CRSP/Med2 was determined to 31 A resolution using electron microscopy and single-particle reconstruction techniques. Despite lacking both Med220 and Med70, CRSP/Med2 displays potent, activator-dependent transcriptional coactivator function in response to VP16, Sp1, and Sp1/SREBP-1a in vitro using chromatin templates. However, CRSP/Med2 is unable to potentiate activated transcription from a vitamin D receptor-responsive promoter, which requires interaction with Med220 for coactivator recruitment, whereas VDR-directed activation by CRSP/Med occurs normally. Thus, it appears that CRSP/Med may be regulated by a combinatorial assembly mechanism that allows promoter-selective function upon exchange of specific coactivator targets.

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