title: 7SK snRNA-mediated, gene-specific cooperativity of HMGA1 and P-TEFb.
abstract: 7SK small-nuclear RNA has been shown to negatively regulate P-TEFb transcription elongation on the one hand and control HMGA1 transcription initiation and chromatin remodeling on the other. The non-coding 7SK RNA thereby directly interacts with both factors through different regions. While the loop 2 of the RNA specifically binds to the first HMGA1 A/T hook, thereby competing with DNA binding to the same domain, loops 1, 3 and 4 are involved in P-TEFb interaction. This raises the question of whether HMGA1 and P-TEFb cooperate during gene transcription. Using transcriptome profiling, we have identifed genes that are oppositely regulated by 7SK RNA over-expression versus shRNA mediated knock-down. Inhibition of P-TEFb by competitive expression of a dominant-negative Cdk9 protein leads to highly similar changes in global gene expression as the over-expression of 7SK RNA, confirming the importance of P-TEFb inhibition by 7SK RNA. Furthermore, we have similarly assembled genes affected concomitantly by HMGA1 over-expression. HMGA1 and P-TEFb, in the case of select target genes, show strong cooperation in transcriptional activation. Finally, we provide evidence for 7SK RNA complexes containing simultaneously HMGA1 and P-TEFb. 7SK RNA thus establishes gene-dependent plasticity between HMGA1 chromatin remodeling and transcription initiation and P-TEFb transcription elongation.
authors.affiliation: Institut des Hautes Études Scientifiques & Centre National de la Recherche Scientifique, Bures sur Yvette, France.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Eilebrecht
authors.forename: Bernd-Joachim
authors.initials: BJ
authors.lastname: Benecke
authors.forename: Arndt
authors.initials: A
authors.lastname: Benecke
mesh_terms: D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D042863:Cyclin-Dependent Kinase 9 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D025741:HMGA1a Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D042925:Positive Transcriptional Elongation Factor B / Q000235:genetics / Q000378:metabolism*; D012342:RNA, Small Nuclear / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D012342:RNA, Small Nuclear; D025741:HMGA1a Protein; D042925:Positive Transcriptional Elongation Factor B; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9