Abstract
miRNAs play a central role in numerous pathologies including multiple cancer types. miR-191 has predominantly been studied as an oncogene, but the role of miR-191 in the proliferation of primary cells is not well characterized, and the miR-191 targetome has not been experimentally profiled. Here we utilized RNA induced silencing complex immunoprecipitations as well as gene expression profiling to construct a genome wide miR-191 target profile. We show that miR-191 represses proliferation in primary human fibroblasts, identify multiple proto-oncogenes as novel miR-191 targets, including CDK9, NOTCH2, and RPS6KA3, and present evidence that miR-191 extensively mediates target expression through coding sequence (CDS) pairing. Our results provide a comprehensive genome wide miR-191 target profile, and demonstrate miR-191’s regulation of primary human fibroblast proliferation.
Highlights
The ability of mammalian cells to transition from a quiescent to a proliferative state is a fundamental aspect of normal cell biology, and forms the basis for diverse physiological processes such as lymphocyte activation, hepatocyte regeneration, and wound healing [1,2,3,4]
We show that miR-191 regulates proliferation in primary human fibroblasts and show by experimental analysis that it targets a number of proto-oncogenes
Constructing genome-wide target profiles as we have done in this work, aids in refining our understanding of miRNA target pairing rules and in improving prediction algorithms
Summary
The ability of mammalian cells to transition from a quiescent to a proliferative state is a fundamental aspect of normal cell biology, and forms the basis for diverse physiological processes such as lymphocyte activation, hepatocyte regeneration, and wound healing [1,2,3,4]. The pathways that control proliferation in normal cells are generally perturbed in cancer, and many cell cycle regulators that control reentry and progression through the cell cycle are altered in cancer cells [5, 6]. Primary human dermal fibroblasts are an exceptional model to study the genetic pathways that regulate proliferation in natural physiological processes and in cancer progression. Primary fibroblasts may be induced to enter or exit a quiescent state in response to exposure to or deprivation of serum containing growth factors respectively. Fibroblast proliferation plays a PLOS ONE | DOI:10.1371/journal.pone.0126535 May 20, 2015
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