Dual role of Med12 in PRC1-dependent gene repression and ncRNA-mediated transcriptional activation.
Mediator is considered an enhancer of RNA-Polymerase II dependent transcription but its function and regulation in pluripotent mouse embryonic stem cells (mESCs) remains unresolved. One means of controlling the function of Mediator is provided by the binding of the Cdk8 module (Med12, Cdk8, Ccnc and Med13) to the core Mediator. Here we report that Med12 operates together with PRC1 to silence key developmental genes in pluripotency. At the molecular level, while PRC1 represses genes it is also required to assemble ncRNA containing Med12-Mediator complexes. In the course of cellular differentiation the H2A ubiquitin binding protein Zrf1 abrogates PRC1-Med12 binding and facilitates the association of Cdk8 with Mediator. This remodeling of Mediator-associated protein complexes converts Mediator from a transcriptional repressor to a transcriptional enhancer, which then mediates ncRNA-dependent activation of Polycomb target genes. Altogether, our data reveal how the interplay of PRC1, ncRNA and Mediator complexes controls pluripotency and cellular differentiation.
a Laboratory of Molecular Epigenetics, Institute of Molecular Biology (IMB) , Mainz , Germany.
Thaleia
T
Papadopoulou
a Laboratory of Molecular Epigenetics, Institute of Molecular Biology (IMB) , Mainz , Germany.
Aysegül
A
Kaymak
b Bioinformatics Core Facility, Institute of Molecular Biology (IMB) , Mainz , Germany.
Sergi
S
Sayols
a Laboratory of Molecular Epigenetics, Institute of Molecular Biology (IMB) , Mainz , Germany.
Holger
H
Richly
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D056745:Cyclin C / Q000235:genetics / Q000378:metabolism; D056850:Cyclin-Dependent Kinase 8 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056892:Mediator Complex / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018832:Molecular Chaperones; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D063146:Polycomb-Group Proteins / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D022661:RNA, Untranslated / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins; D015398:Signal Transduction; D015533:Transcriptional Activation
C503675:Ccnc protein, mouse; D056745:Cyclin C; D004268:DNA-Binding Proteins; C097474:Dnajc2 protein, mouse; D050956:HSP40 Heat-Shock Proteins; C539582:Med12 protein, mouse; C519602:Med13 protein, mouse; D056892:Mediator Complex; D018832:Molecular Chaperones; D063146:Polycomb-Group Proteins; D022661:RNA, Untranslated; D016601:RNA-Binding Proteins; C524803:Cdk8 protein, mouse; D056850:Cyclin-Dependent Kinase 8; D012319:RNA Polymerase II
Polycomb; Mediator; Cdk8; stem cell; pluripotency; differentiation; Zrf1; ncRNA