title: MicroRNAs in the growth plate are responsive to nutritional cues: association between miR-140 and SIRT1.
abstract: MicroRNAs (miRNAs) have been reported to be involved in a variety of functions, including skeletal development and longitudinal growth. The aim of this study was to investigate the role of miRNAs in food-restriction-induced growth attenuation and nutrition-induced catch-up growth in the epiphyseal growth plate (EGP). Prepubertal rats were fed ad libitum or were subjected to 40% food restriction for 10 days followed by a renewal of the regular food supply. At sacrifice, tibial EGPs were excised, and the total RNA was extracted and loaded on miRNA microarrays. The miRNA microarray yielded more than 400 miRNAs that are expressed in the EGP of mature animals. Results were confirmed by quantitative polymerase chain reaction. Chondrocyte-specific miR-140-3p showed the highest expression in the mature EGP, and it was one of the few miRNAs that were significantly reduced following nutrition restriction. Changes in predicted miRNA targets were then followed with Western immunoblotting. Direct binding was demonstrated using exogenous miRNA, the 3'UTR of the target mRNA and a luciferase reporter assay. Nutrition restriction induced an increase in the level of the miR-140-3p target, NAD+-dependent SIRT1. This study is the first to show that SIRT1 and miRNAs expressed in the mature EGP are responsive to nutritional cues. Nutrition-induced epigenetic regulation of growth activates two parts of the epigenetic world - miRNAs and histone deacetylases - that are interconnected. Deciphering the role of epigenetic regulation in growth may open a new era of research and pave the way for the development of new treatments for children with growth disorders.
authors.affiliation: Felsenstein Medical Research Center, Petach Tikva, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
authors.forename: Rakefet
authors.initials: R
authors.lastname: Pando
authors.forename: Naomi
authors.initials: N
authors.lastname: Even-Zohar
authors.forename: Biana
authors.initials: B
authors.lastname: Shtaif
authors.forename: Liat
authors.initials: L
authors.lastname: Edry
authors.forename: Noam
authors.initials: N
authors.lastname: Shomron
authors.forename: Moshe
authors.initials: M
authors.lastname: Phillip
authors.forename: Galia
authors.initials: G
authors.lastname: Gat-Yablonski
mesh_terms: D020413:3' Untranslated Regions; D000824:Animal Nutritional Physiological Phenomena / Q000235:genetics*; D000818:Animals; D019902:Chondrocytes / Q000502:physiology; D044127:Epigenesis, Genetic; D006132:Growth Plate / Q000254:growth & development* / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D018969:Insulin-Like Growth Factor Binding Proteins; C580706:MIRN140 microRNA, rat; D035683:MicroRNAs; C102529:insulin-like growth factor binding protein-related protein 1; C548904:insulin-like growth factor-1, rat; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; C559944:HDAC4 protein, rat; D006655:Histone Deacetylases