The functions of microRNAs in pluripotency and reprogramming.

1] Department of Chemical Physiology, The Scripps Research Institute and the Center for Regenerative Medicine, La Jolla, California 92037, USA [2].
Nature Cell Biology (Impact Factor: 20.06). 11/2012; 14(11):1114-21. DOI: 10.1038/ncb2613
Source: PubMed


Available from: Jeanne F Loring, Jun 15, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Factor induced reprogramming of fibroblasts is an orchestrated but inefficient process. At the epigenetic level, it results in drastic chromatin changes to erase the existing somatic ‘‘memory’’ and to establish the pluripotent state. Accordingly, alterations of chromatin regulators including Ezh2 influence iPSC generation. While the role of individual transcription factors in resetting the chromatin landscape during iPSC generation is increasingly evident, their engagement with chromatin modulators remains to be elucidated. In the current study, we demonstrate that histone methyl transferase activity of Ezh2 is required for mesenchymal to epithelial transition (MET) during human iPSC generation. We show that the H3K27me3 activity favors induction of pluripotency by transcriptionally targeting the TGF- b signaling pathway. We also demonstrate that the Ezh2 negatively regulates the expression of pro-EMT miRNA’s such as miR-23a locus during MET. Unique association of Ezh2 with c-Myc was required to silence the aforementioned circuitry. Collectively, our findings provide a mechanistic understanding by which Ezh2 restrictsthesomaticprogrammeduringearlyphaseofcellularreprogrammingandestablishtheimportance of Ezh2 dependent H3K27me3 activity in transcriptional and miRNA modulation during human iPSC generation.
    5th Meeting of the Asian Forum of Chromosome and Chromatin Biology; 01/2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: Gastric cancer (GC) is one of the most common cancers and the leading cause of cancer-related deaths globally. The discovery of microRNAs (miRNAs) provides a new avenue for GC diagnostic and treatment regiments. Currently, a large number of miRNAs have been reported to be associated with the progression of GC, among which miR-378 has been examined to be downregulated in GC tissues and several cell lines. However, the function of miR-378 on GC cells and the mechanisms were less known. Here we found that ectopic expression of miR-378 could inhibit cell proliferation, cell cycle progression, cell migration as well as invasion, and induced cell apoptosis in GC cell line MGC-803. Moreover, we found that oncogene mitogen-activated protein kinase 1 (MAPK1) was a target gene of miR-378 in GC cells, and the tumor-suppressive role of miR-378 might be achieved by the direct interaction with MAPK1. Taken together, our results showed that miR-378 might act as tumor suppressors in GC, and it may provide novel diagnostic and therapeutic options for human GC clinical operation in the future.
    10/2013; 20(12):557-64. DOI:10.3727/096504013X13775486749254
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The small noncoding RNAs (sncRNAs) are considered as post-transcriptional key regulators of male germ cell development. In addition to microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs), other sncRNAs generated from small nucleolar RNAs (snoRNAs), tRNAs, or rRNAs processing may also play important regulatory roles in spermatogenesis. By next-generation sequencing (NGS), we characterized the sncRNA populations detected at three milestone stages in male germ differentiation: primordial germ cells (PGCs), pubertal spermatogonia cells, and mature spermatozoa. To assess their potential transmission through the spermatozoa during fertilization, the sncRNAs of mouse oocytes and zygotes were also analyzed. Both, microRNAs and snoRNA-derived small RNAs are abundantly expressed in PGCs but transiently replaced by piRNAs in spermatozoa and endo-siRNAs in oocytes and zygotes. Exhaustive analysis of miRNA sequence variants also shows an increment of noncanonical microRNA forms along male germ cell differentiation. RNAs-derived from tRNAs and rRNAs interacting with PIWI proteins are not generated by the ping-pong pathway and could be a source of primary piRNAs. Moreover, our results strongly suggest that the small RNAs-derived from tRNAs and rRNAs are interacting with PIWI proteins, and specifically with MILI. Finally, computational analysis revealed their potential involvement in post-transcriptional regulation of mRNA transcripts suggesting functional convergence among different small RNA classes in germ cells and zygotes. © 2015 García-López et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.
    RNA 03/2015; 21(5). DOI:10.1261/rna.048215.114 · 4.62 Impact Factor