title: Modulation of gene expression via overlapping binding sites exerted by ZNF143, Notch1 and THAP11.
abstract: ZNF143 is a zinc-finger protein involved in the transcriptional regulation of both coding and non-coding genes from polymerase II and III promoters. Our study deciphers the genome-wide regulatory role of ZNF143 in relation with the two previously unrelated transcription factors Notch1/ICN1 and thanatos-associated protein 11 (THAP11) in several human and murine cells. We show that two distinct motifs, SBS1 and SBS2, are associated to ZNF143-binding events in promoters of >3000 genes. Without co-occupation, these sites are also bound by Notch1/ICN1 in T-lymphoblastic leukaemia cells as well as by THAP11, a factor involved in self-renewal of embryonic stem cells. We present evidence that ICN1 binding overlaps with ZNF143 binding events at the SBS1 and SBS2 motifs, whereas the overlap occurs only at SBS2 for THAP11. We demonstrate that the three factors modulate expression of common target genes through the mutually exclusive occupation of overlapping binding sites. The model we propose predicts that the binding competition between the three factors controls biological processes such as rapid cell growth of both neoplastic and stem cells. Overall, our study establishes a novel relationship between ZNF143, THAP11 and ICN1 and reveals important insights into ZNF143-mediated gene regulation.
authors: Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS, IBMC, 15 rue René Descartes, 67084 Strasbourg, France.
authors: Richard Patryk
authors: RP
authors: Ngondo-Mbongo
authors: Evelyne
authors: E
authors: Myslinski
authors: Jon C
authors: JC
authors: Aster
authors: Philippe
authors: P
authors: Carbon
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D059372:Nucleotide Motifs; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D006657:Histones; D051741:Kruppel-Like Transcription Factors; D051881:Receptor, Notch1; D012097:Repressor Proteins; C498470:THAP11 protein, human; C530078:Thap11 protein, mouse; D015534:Trans-Activators; C114253:ZNF143 protein, human; C114252:ZNF76 protein, human; D012319:RNA Polymerase II