a microrna network regulates proliferative timing and extracellular matrix synthesis during cellular quiescence in fibroblasts微网络调节增殖的时机和细胞外基质合成在成纤维细胞细胞静止.pdfVIP

Suh et al. Genome Biology 2012, 13:R121 /2012/13/12/R121 RESEARCH Open Access A microRNA network regulates proliferative timing and extracellular matrix synthesis during cellular quiescence in fibroblasts Eric J Suh, Matthew Y Remillard, Aster Legesse-Miller, Elizabeth L Johnson, Johanna MS Lemons, Talia R Chapman, * Joshua J Forman, Mina Kojima, Eric S Silberman and Hilary A Coller 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 ev