Article

Mediator Requirement for Both Recruitment and Postrecruitment Steps in Transcription Initiation

Molecular Biology Institute and Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, 611 Young Drive East, Los Angeles, California 90095, USA.
Molecular Cell (Impact Factor: 14.46). 04/2005; 17(5):683-94. DOI: 10.1016/j.molcel.2005.02.010
Source: PubMed

ABSTRACT Mediator complexes are required for activators to stimulate Pol II preinitiation complex assembly on an associated promoter. We show here that for the mouse Egr1 gene, controlled largely by MAP kinase phosphorylation of the ELK1 transcription factor, the MED23 Mediator subunit that interacts with phospho-ELK1 is also required to stimulate Pol II initiation at a step subsequent to preinitiation complex assembly. In Med23-/- cells, histone acetylation, methylation, and chromatin remodeling complex association at the Egr1 promoter were equivalent to that of wild-type cells, yet Egr1 induction was greatly reduced. MAP kinase activation stimulated Pol II and GTF promoter binding. However, the difference in factor binding between wild-type and mutant cells was much less than the difference in transcription, and Pol II remained localized to the promoter in mutant cells. These results indicate that an interaction with MED23 stimulates initiation by promoter bound Pol II in addition to Pol II and GTF recruitment.

Full-text

Available from: Hiroshi Handa, May 29, 2015
0 Followers
 · 
95 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The RNA polymerase II (Pol II) enzyme transcribes all protein-coding and most non-coding RNA genes and is globally regulated by Mediator - a large, conformationally flexible protein complex with a variable subunit composition (for example, a four-subunit cyclin-dependent kinase 8 module can reversibly associate with it). These biochemical characteristics are fundamentally important for Mediator's ability to control various processes that are important for transcription, including the organization of chromatin architecture and the regulation of Pol II pre-initiation, initiation, re-initiation, pausing and elongation. Although Mediator exists in all eukaryotes, a variety of Mediator functions seem to be specific to metazoans, which is indicative of more diverse regulatory requirements.
    Nature Reviews Molecular Cell Biology 02/2015; 16(3). DOI:10.1038/nrm3951 · 36.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pre-messenger RNA (mRNA) processing, generally including capping, mRNA splicing, and cleavage-polyadenylation, is physically and functionally associated with transcription. The reciprocal coupling between transcription and mRNA processing ensures the efficient and regulated gene expression and editing. Multiple transcription factors/cofactors and mRNA processing factors are involved in the coupling process. This review focuses on several classic examples and recent advances that enlarge our understanding of how the transcriptional factors or cofactors, especially the Mediator complex, contribute to the RNA Pol II elongation, mRNA splicing, and polyadenylation.For further resources related to this article, please visit the WIREs website.Conflict of interest: The authors have declared no conflicts of interest for this article
    WIREs RNA 12/2014; 6(2). DOI:10.1002/wrna.1273 · 6.15 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Unraveling the mechanisms underlying early neural differentiation of embryonic stem cells (ESCs) is crucial to developing cell-based therapies of neurodegenerative diseases. Neural fate acquisition is proposed to be controlled by a 'default' mechanism, for which the molecular regulation is not well understood. In this study, we investigated the functional roles of Mediator Med23 in pluripotency and lineage commitment of murine ESCs. Unexpectedly, we found that, despite the largely unchanged pluripotency and self-renewal of ESCs, Med23 depletion rendered the cells prone to neural differentiation in different differentiation assays. Knockdown of two other Mediator subunits, Med1 and Med15, did not alter the neural differentiation of ESCs. Med15 knockdown selectively inhibited endoderm differentiation, suggesting the specificity of cell fate control by distinctive Mediator subunits. Gene profiling revealed that Med23 depletion attenuated BMP signaling in ESCs. Mechanistically, MED23 modulated Bmp4 expression by controlling the activity of ETS1, which is involved in Bmp4 promoter-enhancer communication. Interestingly, med23 knockdown in zebrafish embryos also enhanced neural development at early embryogenesis, which could be reversed by co-injection of bmp4 mRNA. Taken together, our study reveals an intrinsic, restrictive role of MED23 in early neural development, thus providing new molecular insights for neural fate determination. © 2015. Published by The Company of Biologists Ltd.
    Development 01/2015; 142(3). DOI:10.1242/dev.112946 · 6.27 Impact Factor