title: The transcriptional co-repressor TLE3 suppresses basal signaling on a subset of estrogen receptor α target genes.
abstract: Chromatin constitutes a repressive barrier to the process of ligand-dependent transcriptional activity of nuclear receptors. Nucleosomes prevent the binding of estrogen receptor α (ERα) in absence of ligand and thus represent an important level of transcriptional regulation. Here, we show that in breast cancer MCF-7 cells, TLE3, a co-repressor of the Groucho/Grg/TLE family, interacts with FoxA1 and is detected at regulatory elements of ERα target genes in absence of estrogen. As a result, the chromatin is maintained in a basal state of acetylation, thus preventing ligand-independent activation of transcription. In absence of TLE3, the basal expression of ERα target genes induced by E2 is increased. At the TFF1 gene, the recruitment of TLE3 to the chromatin is FoxA1-dependent and prevents ERα and RNA polymerase II recruitment to TFF1 gene regulatory elements. Moreover, the interaction of TLE3 with HDAC2 results in the maintenance of acetylation at a basal level. We also provide evidence that TLE3 is recruited at several other regulatory elements of ERα target genes and is probably an important co-regulator of the E2 signaling pathway. In sum, our results describe a mechanism by which TLE3 affects ligand dependency in ERα-regulated gene expression via its binding restricting function and its role in gene regulation by histone acetylation.
authors.affiliation: Département de biologie, Faculté des sciences, Université de Sherbrooke, 2500 boulevard de l'Université, Sherbrooke, Québec J1K 2R1, Canada.
authors.forename: Maïka
authors.initials: M
authors.lastname: Jangal
authors.affiliation: Département de biologie, Faculté des sciences, Université de Sherbrooke, 2500 boulevard de l'Université, Sherbrooke, Québec J1K 2R1, Canada.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Couture
authors.affiliation: Département de biologie, Faculté des sciences, Université de Sherbrooke, 2500 boulevard de l'Université, Sherbrooke, Québec J1K 2R1, Canada.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bianco
authors.affiliation: Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medecine, Imperial College Hammersmith, London W12 0NN, UK.
authors.forename: Luca
authors.initials: L
authors.lastname: Magnani
authors.affiliation: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson way, Cambridge CB2 0RE, UK.
authors.forename: Hisham
authors.initials: H
authors.lastname: Mohammed
authors.affiliation: Département de biologie, Faculté des sciences, Université de Sherbrooke, 2500 boulevard de l'Université, Sherbrooke, Québec J1K 2R1, Canada nicolas.gevry@usherbrooke.ca.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gévry
mesh_terms: D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D056970:Co-Repressor Proteins / Q000378:metabolism* / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005786:Gene Expression Regulation; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000502:physiology; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D050436:Regulatory Elements, Transcriptional; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D056970:Co-Repressor Proteins; D047628:Estrogen Receptor alpha; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D006657:Histones; C570667:TLE3 protein, human; D006655:Histone Deacetylases