title: MicroRNA-mediated regulation of extracellular matrix formation modulates somatic cell reprogramming.
abstract: Somatic cells can be reprogrammed to reach an embryonic stem cell-like state by overexpression of defined factors. Recent studies have greatly improved the efficiency of the reprogramming process but the underlying mechanisms regulating the transition from a somatic to a pluripotent state are still relatively unknown. MicroRNAs (miRs) are small noncoding RNAs that primarily regulate target gene expression post-transcriptionally. Here we present a systematic and comprehensive study of microRNAs in mouse embryonic fibroblasts (MEFs) during the early stage of cell fate decisions and reprogramming to a pluripotent state, in which significant transcriptional and epigenetic changes occur. One microRNA found to be highly induced during this stage of reprogramming, miR-135b, targeted the expression of extracellular matrix (ECM) genes including Wisp1 and Igfbp5. Wisp1 was shown to be a key regulator of additional ECM genes that serve as barriers to reprogramming. Regulation of Wisp 1 is likely mediated through biglycan, a glycoprotein highly expressed in MEFs that is silenced in reprogrammed cells. Collectively, this report reveals a novel link between microRNA-mediated regulation of ECM formation and somatic cell reprogramming, and demonstrates that microRNAs are powerful tools to dissect the intracellular and extracellular molecular mechanisms of reprogramming.
authors.affiliation: Program for RNA Biology, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Zhonghan
authors.initials: Z
authors.lastname: Li
authors.affiliation: Program for RNA Biology, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA Department of Bioengineering, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Dang
authors.affiliation: Program for RNA Biology, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California 92093, USA.
authors.forename: Kung-Yen
authors.initials: KY
authors.lastname: Chang
authors.affiliation: Program for RNA Biology, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California 92093, USA trana@ucsd.edu.
authors.forename: Tariq M
authors.initials: TM
authors.lastname: Rana
mesh_terms: D000818:Animals; D055511:CCN Intercellular Signaling Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D065150:Cellular Reprogramming / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000378:metabolism; D044127:Epigenesis, Genetic; D005109:Extracellular Matrix / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics
chemical_list: D055511:CCN Intercellular Signaling Proteins; C492067:CCN4 protein, mouse; D035683:MicroRNAs; C549289:Mirn135 microRNA, mouse; D011518:Proto-Oncogene Proteins
keywords: ECM; iPS; miRNA