title: Tumorigenesis by Meis1 overexpression is accompanied by a change of DNA target-sequence specificity which allows binding to the AP-1 element.
abstract: Meis1 overexpression induces tumorigenicity but its activity is inhibited by Prep1 tumor suppressor. Why does overexpression of Meis1 cause cancer and how does Prep1 inhibit? Tumor profiling and ChIP-sequencing data in a genetically-defined set of cell lines show that: 1) The number of Meis1 and Prep1 DNA binding sites increases linearly with their concentration resulting in a strong increase of "extra" target genes. 2) At high concentration, Meis1 DNA target specificity changes such that the most enriched consensus becomes that of the AP-1 regulatory element, whereas the specific OCTA consensus is not enriched because diluted within the many extra binding sites. 3) Prep1 inhibits Meis1 tumorigenesis preventing the binding to many of the "extra" genes containing AP-1 sites. 4) The overexpression of Prep1, but not of Meis1, changes the functional genomic distribution of the binding sites, increasing seven fold the number of its "enhancer" and decreasing its "promoter" targets. 5) A specific Meis1 "oncogenic" and Prep1 "tumor suppressing" signature has been identified selecting from the pool of genes bound by each protein those whose expression was modified uniquely by the "tumor-inducing" Meis1 or tumor-inhibiting Prep1 overexpression. In both signatures, the enriched gene categories are the same and are involved in signal transduction. However, Meis1 targets stimulatory genes while Prep1 targets genes that inhibit the tumorigenic signaling pathways.
authors.affiliation: IFOM, FIRC Institute of Molecular Oncology, IFOM-IEO Campus, Milano, Italy.|Present Address: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Leila
authors.initials: L
authors.lastname: Dardaei
authors.affiliation: IFOM, FIRC Institute of Molecular Oncology, IFOM-IEO Campus, Milano, Italy.|Department of Experimental Cardiology, Russian Cardiology Research and Production Complex, Moscow, Russia.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Penkov
authors.affiliation: IFOM, FIRC Institute of Molecular Oncology, IFOM-IEO Campus, Milano, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Mathiasen
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.
authors.forename: Pranami
authors.initials: P
authors.lastname: Bora
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.
authors.forename: Marco J
authors.initials: MJ
authors.lastname: Morelli
authors.affiliation: IFOM, FIRC Institute of Molecular Oncology, IFOM-IEO Campus, Milano, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Blasi
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D018398:Homeodomain Proteins; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; C491412:Pknox1 protein, mouse; D018808:Transcription Factor AP-1
keywords: AP-1; ChIP-seq; Meis1; Prep1; tumorigenesis