Mediator expression profiling epistasis reveals a signal transduction pathway with antagonistic submodules and highly specific downstream targets

Jeroen Van De Peppel, Nienke Kettelarij, Harm Van Bakel, Thessa T.J.P. Kockelkorn, Dik Van Leenen, Frank C.P. Holstege

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

172 Citaten (Scopus)

Samenvatting

Mediator is an evolutionarily conserved coregulator of RNA polymerase II transcription. Microarray structure-function analysis of S. cerevisiae Mediator reveals functional antagonism between the cyclin-dependent kinase (Cdk) submodule and components from the Tail (Med15, Med2, Med3), Head (Med20, Med18), and Middle (Med31). Certain genes exhibit increased or decreased expression, depending on which subunit is deleted. Epistasis analysis with expression-profile phenotypes shows that MED2 and MED18 are downstream of CDK8. Strikingly, Cdk8-mediated modification of a single amino acid within Mediator represses the regulon of a single transcription factor, Rcs1/Aft1. Highly specific gene regulation is thought to be determined by activators and combinatorial use of cofactors. Here, subtle modification of the general transcription machinery through one of its own components is shown to determine highly specific expression patterns. Expression profiling can therefore precisely map regulatory cascades, and our findings support a role for Mediator as a direct processor of signaling pathways for determining specificity.

Originele taal-2Engels
Pagina's (van-tot)511-522
Aantal pagina's12
TijdschriftMolecular Cell
Volume19
Nummer van het tijdschrift4
DOI's
StatusGepubliceerd - 19 aug. 2005
Extern gepubliceerdJa

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