title: A novel mechanism of post-translational modulation of HMGA functions by the histone chaperone nucleophosmin.
abstract: High Mobility Group A are non-histone nuclear proteins that regulate chromatin plasticity and accessibility, playing an important role both in physiology and pathology. Their activity is controlled by transcriptional, post-transcriptional, and post-translational mechanisms. In this study we provide evidence for a novel modulatory mechanism for HMGA functions. We show that HMGAs are complexed in vivo with the histone chaperone nucleophosmin (NPM1), that this interaction requires the histone-binding domain of NPM1, and that NPM1 modulates both DNA-binding affinity and specificity of HMGAs. By focusing on two human genes whose expression is directly regulated by HMGA1, the Insulin receptor (INSR) and the Insulin-like growth factor-binding protein 1 (IGFBP1) genes, we demonstrated that occupancy of their promoters by HMGA1 was NPM1-dependent, reflecting a mechanism in which the activity of these cis-regulatory elements is directly modulated by NPM1 leading to changes in gene expression. HMGAs need short stretches of AT-rich nucleosome-free regions to bind to DNA. Therefore, many putative HMGA binding sites are present within the genome. Our findings indicate that NPM1, by exerting a chaperoning activity towards HMGAs, may act as a master regulator in the control of DNA occupancy by these proteins and hence in HMGA-mediated gene expression.
authors.affiliation: Department of Life Sciences, University of Trieste, Trieste, 34127, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Arnoldo
authors.affiliation: Department of Life Sciences, University of Trieste, Trieste, 34127, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Sgarra
authors.affiliation: Department of Health Sciences, University "Magna Græcia" of Catanzaro, Catanzaro, 88100, Italy.
authors.forename: Eusebio
authors.initials: E
authors.lastname: Chiefari
authors.affiliation: Department of Health Sciences, University "Magna Græcia" of Catanzaro, Catanzaro, 88100, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Iiritano
authors.affiliation: Department of Health Sciences, University "Magna Græcia" of Catanzaro, Catanzaro, 88100, Italy.
authors.forename: Biagio
authors.initials: B
authors.lastname: Arcidiacono
authors.affiliation: Department of Life Sciences, University of Trieste, Trieste, 34127, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pegoraro
authors.affiliation: Department of Life Sciences, University of Trieste, Trieste, 34127, Italy.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Pellarin
authors.affiliation: Department of Health Sciences, University "Magna Græcia" of Catanzaro, Catanzaro, 88100, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Brunetti
authors.affiliation: Department of Life Sciences, University of Trieste, Trieste, 34127, Italy.
authors.forename: Guidalberto
authors.initials: G
authors.lastname: Manfioletti
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D024003:HMGA Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D056488:Histone Chaperones / Q000378:metabolism; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000090243:Nucleophosmin; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D014158:Transcription, Genetic
chemical_list: D024003:HMGA Proteins; D056488:Histone Chaperones; C032231:IGFBP1 protein, human; D018970:Insulin-Like Growth Factor Binding Protein 1; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D000090243:Nucleophosmin; D004247:DNA; D011972:Receptor, Insulin