title: The regulatory network menin-microRNA 26a as a possible target for RNA-based therapy of bone diseases.
abstract: MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression, interplaying with transcription factors in complex regulatory networks. Menin is the product of the MEN1 oncosuppressor gene, responsible for multiple endocrine neoplasia type 1 syndrome. Recent data suggest that menin functions as a general regulator of transcription. Menin expression modulates mesenchymal cell commitment to the myogenic or osteogenic lineages. The microRNA 26a (miR-26a) modulates the expression of SMAD1 protein during the osteoblastic differentiation of human adipose tissue-derived stem cells (hADSCs). We used siRNA silencing against MEN1 mRNA and pre-miR-26 mimics to study the interplay between them and to investigate the interplay between menin and miR-26a as regulators of osteogenic differentiation in the hADSCs. We found that in hADSCs the siRNA-induced silencing of MEN1 mRNA resulted in a down regulation of miR-26a, with a consequent up-regulation of SMAD1 protein. Chromatin immunoprecipitation (ChIP) showed that menin occupies the miR-26-a gene promoter, thus inducing its expression and confirming that menin is a positive regulator of miR-26a. In conclusion, results from this study evidenced, for the first time, a direct interaction between menin transcription factor and miRNA, interaction that seems to play a pivotal role during the hADSCs osteogenesis, thus suggesting a novel target for bone disease RNA-based therapy.
authors.affiliation: Metabolic Bone Unit, Department of Internal Medicine, University of Florence, Florence, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Luzi
authors.forename: Francesca
authors.initials: F
authors.lastname: Marini
authors.forename: Isabella
authors.initials: I
authors.lastname: Tognarini
authors.forename: Gianna
authors.initials: G
authors.lastname: Galli
authors.forename: Alberto
authors.initials: A
authors.lastname: Falchetti
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Brandi
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000273:Adipose Tissue / Q000166:cytology; D000469:Alkaline Phosphatase / Q000378:metabolism; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D001847:Bone Diseases / Q000628:therapy; D002454:Cell Differentiation / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D015870:Gene Expression; D053263:Gene Regulatory Networks; D017930:Genes, Reporter; D006801:Humans; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology*
chemical_list: D020413:3' Untranslated Regions; D000469:Alkaline Phosphatase; D000943:Antigens, Differentiation; D049410:Luciferases, Renilla; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D051898:Smad1 Protein; C105373:MEN1 protein, human; C528163:MIRN26 microRNA, human; C497399:SMAD1 protein, human