A microRNA network regulates proliferative timing and extracellular matrix synthesis during cellular quiescence in fibroblasts

摘要

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 micro RNAs as regulators of the cellular functions of quiescent human fibroblasts. Results: Using microarrays, we discovered that the expression of the majority of profiled micro RNAs differed between proliferating and quiescent fibroblasts. Fibroblasts induced into quiescence by contact inhibition or serum starvation had similar micro RNA profiles, indicating common changes induced by distinct quiescence signals. By analyzing the gene expression patterns of micro RNA target genes with quiescence, we discovered a strong regulatory function for mi R-29, which is downregulated with quiescence. Using microarrays and immunoblotting, we confirmed that mi R-29 targets genes encoding collagen and other extracellular matrix proteins and that those target genes are induced in quiescence. In addition, overexpression of mi R-29 resulted in more rapid cell cycle re- entry from quiescence. We also found that let-7 and mi R-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: micro RNAs 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.