title: HMGA1 recruits CTIP2-repressed P-TEFb to the HIV-1 and cellular target promoters.
abstract: Active positive transcription elongation factor b (P-TEFb) is essential for cellular and human immunodeficiency virus type 1 (HIV-1) transcription elongation. CTIP2 represses P-TEFb activity in a complex containing 7SK RNA and HEXIM1. Recently, the inactive 7SK/P-TEFb small nuclear RNP (snRNP) has been detected at the HIV-1 core promoter as well as at the promoters of cellular genes, but a recruiting mechanism still remains unknown to date. Here we show global synergy between CTIP2 and the 7SK-binding chromatin master-regulator HMGA1 in terms of P-TEFb-dependent endogenous and HIV-1 gene expression regulation. While CTIP2 and HMGA1 concordingly repress the expression of cellular 7SK-dependent P-TEFb targets, the simultaneous knock-down of CTIP2 and HMGA1 also results in a boost in Tat-dependent and independent HIV-1 promoter activity. Chromatin immunoprecipitation experiments reveal a significant loss of CTIP2/7SK/P-TEFb snRNP recruitment to cellular gene promoters and the HIV-1 promoter on HMGA1 knock-down. Our findings not only provide insights into a recruiting mechanism for the inactive 7SK/P-TEFb snRNP, but may also contribute to a better understanding of viral latency.
authors.affiliation: Vaccine Research Institute, INSERM U955, Institut Mondor de Recherche Biomédicale, 8 rue du général Sarrail, 94011 Créteil, France, Institut des Hautes Études Scientifiques-Centre National de la Recherche Scientifique, 35 route de Chartres, 91440 Bures sur Yvette, France, Institut de Parasitologie et de Pathologie Tropicale, Fédération de Médecine Translationnelle, University of Strasbourg, 3 rue Koeberlé, 67000 Strasbourg, France, IUT Louis Pasteur, 1 Allée d'Athénes, 67300 Schiltigheim, France, Université Libre de Bruxelles (ULB), Service of Molecular Virology, Institute for Molecular Biology and Medicine (IBMM), 12 rue des Profs Jeener et Brachet, 6041 Gosselies, Belgium, Institut Universitaire de France-IUF, Paris, France and CNRS UMR 7224, Université Pierre et Marie Curie, 7 quai Saint Bernard, 75005 Paris, France.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Eilebrecht
authors.forename: Valentin
authors.initials: V
authors.lastname: Le Douce
authors.forename: Raphael
authors.initials: R
authors.lastname: Riclet
authors.forename: Brice
authors.initials: B
authors.lastname: Targat
authors.forename: Houda
authors.initials: H
authors.lastname: Hallay
authors.forename: Benot
authors.initials: B
authors.lastname: Van Driessche
authors.forename: Christian
authors.initials: C
authors.lastname: Schwartz
authors.forename: Gwenaëlle
authors.initials: G
authors.lastname: Robette
authors.forename: Carine
authors.initials: C
authors.lastname: Van Lint
authors.forename: Olivier
authors.initials: O
authors.lastname: Rohr
authors.forename: Arndt G
authors.initials: AG
authors.lastname: Benecke
mesh_terms: D002460:Cell Line; D005786:Gene Expression Regulation; D015497:HIV-1 / Q000235:genetics*; D025741:HMGA1a Protein / Q000378:metabolism*; D006801:Humans; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C479740:BCL11B protein, human; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D025741:HMGA1a Protein; D042925:Positive Transcriptional Elongation Factor B