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The Mediator complex and transcription regulation.

Poss ZC, Ebmeier CC, Taatjes DJ - Crit. Rev. Biochem. Mol. Biol. (2013)

Bottom Line: Thus, Mediator is essential for converting biological inputs (communicated by TFs) to physiological responses (via changes in gene expression).We focus on the basics that underlie Mediator function, such as its structure and subunit composition, and describe its broad regulatory influence on gene expression, ranging from chromatin architecture to transcription initiation and elongation, to mRNA processing.We also describe factors that influence Mediator structure and activity, including TFs, non-coding RNAs and the CDK8 module.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of Colorado , Boulder, CO , USA.

ABSTRACT
The Mediator complex is a multi-subunit assembly that appears to be required for regulating expression of most RNA polymerase II (pol II) transcripts, which include protein-coding and most non-coding RNA genes. Mediator and pol II function within the pre-initiation complex (PIC), which consists of Mediator, pol II, TFIIA, TFIIB, TFIID, TFIIE, TFIIF and TFIIH and is approximately 4.0 MDa in size. Mediator serves as a central scaffold within the PIC and helps regulate pol II activity in ways that remain poorly understood. Mediator is also generally targeted by sequence-specific, DNA-binding transcription factors (TFs) that work to control gene expression programs in response to developmental or environmental cues. At a basic level, Mediator functions by relaying signals from TFs directly to the pol II enzyme, thereby facilitating TF-dependent regulation of gene expression. Thus, Mediator is essential for converting biological inputs (communicated by TFs) to physiological responses (via changes in gene expression). In this review, we summarize an expansive body of research on the Mediator complex, with an emphasis on yeast and mammalian complexes. We focus on the basics that underlie Mediator function, such as its structure and subunit composition, and describe its broad regulatory influence on gene expression, ranging from chromatin architecture to transcription initiation and elongation, to mRNA processing. We also describe factors that influence Mediator structure and activity, including TFs, non-coding RNAs and the CDK8 module.

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EM structure of human Mediator compared with human Mediator lacking the MED1 and MED26 subunits. Both complexes are bound to the activation domain of VP16, and each is rendered at their predicted molecular weight (1.2 MDa or 0.9 MDa, respectively). The circled region indicates one area of missing protein density in the complex lacking MED1 and MED26. Note, however, that a pol II interaction surface (dashed yellow line; see text) is maintained in both structures, consistent with a general ability of each complex to activate transcription by VP16 (Taatjes & Tjian, 2004). (see colour version of this figure online at www.informahealthcare.com/bmg).
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f2: EM structure of human Mediator compared with human Mediator lacking the MED1 and MED26 subunits. Both complexes are bound to the activation domain of VP16, and each is rendered at their predicted molecular weight (1.2 MDa or 0.9 MDa, respectively). The circled region indicates one area of missing protein density in the complex lacking MED1 and MED26. Note, however, that a pol II interaction surface (dashed yellow line; see text) is maintained in both structures, consistent with a general ability of each complex to activate transcription by VP16 (Taatjes & Tjian, 2004). (see colour version of this figure online at www.informahealthcare.com/bmg).

Mentions: Although every Mediator subunit knockout reported in mammals has been embryonic lethal (Ito et al., 2002, 2000; Stevens et al., 2002; Tudor et al., 1999; Westerling et al., 2007), cell lines have been derived from knockout embryos in some cases, allowing evaluation of Mediator activity in cellular and in vitro assays. Mouse knockout experiments from the Roeder (Med24 knockout) and Berk labs (Med23 knockout) have revealed that MED23, MED16, and MED24 might form a stable sub-assembly, as loss of either Med23 or Med24 resulted in Mediator complexes with reduced levels of these three subunits (Ito et al., 2002; Stevens et al., 2002). The Roeder group also noted sub-stoichiometric levels of Cdk8 upon loss of Med24 in murine embryonic fibroblasts (MEFs). MED1 represents another Mediator subunit whose absence does not seem to affect complex integrity. Mediator isolated from Med1 knockout MEFs is stable and transcriptionally active (Ito et al., 2000; Malik et al., 2004). It also appears that MED1-deficient Mediator complexes are present endogenously, as shown by the Tjian and Roeder labs (Malik et al., 2004; Taatjes & Tjian, 2004). Notably, endogenous Mediator complexes that lacked MED1 also lacked MED26, suggesting these subunits might form a sub-assembly in Mediator. EM analysis of this complex revealed regions with missing density (Figure 2) compared with the Mediator complex that contained MED1 and MED26 (Taatjes & Tjian, 2004).Figure 2.


The Mediator complex and transcription regulation.

Poss ZC, Ebmeier CC, Taatjes DJ - Crit. Rev. Biochem. Mol. Biol. (2013)

EM structure of human Mediator compared with human Mediator lacking the MED1 and MED26 subunits. Both complexes are bound to the activation domain of VP16, and each is rendered at their predicted molecular weight (1.2 MDa or 0.9 MDa, respectively). The circled region indicates one area of missing protein density in the complex lacking MED1 and MED26. Note, however, that a pol II interaction surface (dashed yellow line; see text) is maintained in both structures, consistent with a general ability of each complex to activate transcription by VP16 (Taatjes & Tjian, 2004). (see colour version of this figure online at www.informahealthcare.com/bmg).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3852498&req=5

f2: EM structure of human Mediator compared with human Mediator lacking the MED1 and MED26 subunits. Both complexes are bound to the activation domain of VP16, and each is rendered at their predicted molecular weight (1.2 MDa or 0.9 MDa, respectively). The circled region indicates one area of missing protein density in the complex lacking MED1 and MED26. Note, however, that a pol II interaction surface (dashed yellow line; see text) is maintained in both structures, consistent with a general ability of each complex to activate transcription by VP16 (Taatjes & Tjian, 2004). (see colour version of this figure online at www.informahealthcare.com/bmg).
Mentions: Although every Mediator subunit knockout reported in mammals has been embryonic lethal (Ito et al., 2002, 2000; Stevens et al., 2002; Tudor et al., 1999; Westerling et al., 2007), cell lines have been derived from knockout embryos in some cases, allowing evaluation of Mediator activity in cellular and in vitro assays. Mouse knockout experiments from the Roeder (Med24 knockout) and Berk labs (Med23 knockout) have revealed that MED23, MED16, and MED24 might form a stable sub-assembly, as loss of either Med23 or Med24 resulted in Mediator complexes with reduced levels of these three subunits (Ito et al., 2002; Stevens et al., 2002). The Roeder group also noted sub-stoichiometric levels of Cdk8 upon loss of Med24 in murine embryonic fibroblasts (MEFs). MED1 represents another Mediator subunit whose absence does not seem to affect complex integrity. Mediator isolated from Med1 knockout MEFs is stable and transcriptionally active (Ito et al., 2000; Malik et al., 2004). It also appears that MED1-deficient Mediator complexes are present endogenously, as shown by the Tjian and Roeder labs (Malik et al., 2004; Taatjes & Tjian, 2004). Notably, endogenous Mediator complexes that lacked MED1 also lacked MED26, suggesting these subunits might form a sub-assembly in Mediator. EM analysis of this complex revealed regions with missing density (Figure 2) compared with the Mediator complex that contained MED1 and MED26 (Taatjes & Tjian, 2004).Figure 2.

Bottom Line: Thus, Mediator is essential for converting biological inputs (communicated by TFs) to physiological responses (via changes in gene expression).We focus on the basics that underlie Mediator function, such as its structure and subunit composition, and describe its broad regulatory influence on gene expression, ranging from chromatin architecture to transcription initiation and elongation, to mRNA processing.We also describe factors that influence Mediator structure and activity, including TFs, non-coding RNAs and the CDK8 module.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of Colorado , Boulder, CO , USA.

ABSTRACT
The Mediator complex is a multi-subunit assembly that appears to be required for regulating expression of most RNA polymerase II (pol II) transcripts, which include protein-coding and most non-coding RNA genes. Mediator and pol II function within the pre-initiation complex (PIC), which consists of Mediator, pol II, TFIIA, TFIIB, TFIID, TFIIE, TFIIF and TFIIH and is approximately 4.0 MDa in size. Mediator serves as a central scaffold within the PIC and helps regulate pol II activity in ways that remain poorly understood. Mediator is also generally targeted by sequence-specific, DNA-binding transcription factors (TFs) that work to control gene expression programs in response to developmental or environmental cues. At a basic level, Mediator functions by relaying signals from TFs directly to the pol II enzyme, thereby facilitating TF-dependent regulation of gene expression. Thus, Mediator is essential for converting biological inputs (communicated by TFs) to physiological responses (via changes in gene expression). In this review, we summarize an expansive body of research on the Mediator complex, with an emphasis on yeast and mammalian complexes. We focus on the basics that underlie Mediator function, such as its structure and subunit composition, and describe its broad regulatory influence on gene expression, ranging from chromatin architecture to transcription initiation and elongation, to mRNA processing. We also describe factors that influence Mediator structure and activity, including TFs, non-coding RNAs and the CDK8 module.

Show MeSH