title: A microRNA network regulates proliferative timing and extracellular matrix synthesis during cellular quiescence in fibroblasts.
abstract: BACKGROUND
  Although quiescence (reversible cell cycle arrest) is a key part in the life history and fate of many mammalian cell types, the mechanisms of gene regulation in quiescent cells are poorly understood. We sought to clarify the role of microRNAs as regulators of the cellular functions of quiescent human fibroblasts.
  
  
  RESULTS
  Using microarrays, we discovered that the expression of the majority of profiled microRNAs differed between proliferating and quiescent fibroblasts. Fibroblasts induced into quiescence by contact inhibition or serum starvation had similar microRNA profiles, indicating common changes induced by distinct quiescence signals. By analyzing the gene expression patterns of microRNA target genes with quiescence, we discovered a strong regulatory function for miR-29, which is downregulated with quiescence. Using microarrays and immunoblotting, we confirmed that miR-29 targets genes encoding collagen and other extracellular matrix proteins and that those target genes are induced in quiescence. In addition, overexpression of miR-29 resulted in more rapid cell cycle re-entry from quiescence. We also found that let-7 and miR-125 were upregulated in quiescent cells. Overexpression of either one alone resulted in slower cell cycle re-entry from quiescence, while the combination of both together slowed cell cycle re-entry even further.
  
  
  CONCLUSIONS
  microRNAs regulate key aspects of fibroblast quiescence including the proliferative state of the cells as well as their gene expression profiles, in particular, the induction of extracellular matrix proteins in quiescent fibroblasts.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Suh
authors.forename: Matthew Y
authors.initials: MY
authors.lastname: Remillard
authors.forename: Aster
authors.initials: A
authors.lastname: Legesse-Miller
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Johnson
authors.forename: Johanna M S
authors.initials: JM
authors.lastname: Lemons
authors.forename: Talia R
authors.initials: TR
authors.lastname: Chapman
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Forman
authors.forename: Mina
authors.initials: M
authors.lastname: Kojima
authors.forename: Eric S
authors.initials: ES
authors.lastname: Silberman
authors.forename: Hilary A
authors.initials: HA
authors.lastname: Coller
mesh_terms: D002453:Cell Cycle; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis* / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism* / Q000502:physiology; D018832:Molecular Chaperones / Q000096:biosynthesis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D016326:Extracellular Matrix Proteins; C531888:MIRN125 microRNA, human; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D018832:Molecular Chaperones; D016212:Transforming Growth Factor beta; C487931:mirnlet7 microRNA, human; D003094:Collagen