microRNAs as novel regulators of stem cell pluripotency and somatic cell reprogramming

Emerging evidence suggests that microRNA (miRNA)‐mediated post‐transcriptional gene regulation plays an essential role in modulating embryonic stem (ES) cell pluripotency maintenance, differentiation, and reprogramming of somatic cells to an ES cell‐like state. Investigations from ES cell‐enriched miRNAs, such as mouse miR‐290 cluster and human miR‐302 cluster, and ES cell‐depleted miRNAs such as let‐7 family miRNAs, revealed a common theme that miRNAs target diverse cellular processes including cell cycle regulators, signaling pathway effectors, transcription factors, and epigenetic modifiers and shape their protein output. The combinatorial effects downstream of miRNA action allow miRNAs to modulate cell‐fate decisions effectively. Furthermore, the transcription and biogenesis of miRNAs are also tightly regulated. Thus, elucidating the interplay between miRNAs and other modes of gene regulation will shed new light on the biology of pluripotent stem cells and somatic cell reprogramming.

[1]  C. Joo,et al.  TUT4 in Concert with Lin28 Suppresses MicroRNA Biogenesis through Pre-MicroRNA Uridylation , 2009, Cell.

[2]  U. Kutay,et al.  Nuclear Export of MicroRNA Precursors , 2004, Science.

[3]  Donald C. Chang,et al.  Regulation of somatic cell reprogramming through inducible mir-302 expression , 2010, Nucleic acids research.

[4]  Thomas Lufkin,et al.  Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb , 2009, Nature Cell Biology.

[5]  Robert L. Judson,et al.  Multiple targets of miR-302 and miR-372 promote reprogramming of human fibroblasts to induced pluripotent stem cells , 2011, Nature Biotechnology.

[6]  Austin G Smith.  A glossary for stem-cell biology , 2006, Nature.

[7]  D. Bartel.  MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[8]  J. Utikal,et al.  Immortalization eliminates a roadblock during cellular reprogramming into iPS cells , 2009, Nature.

[9]  M. Blasco,et al.  The Ink4/Arf locus is a barrier for iPS cell reprogramming , 2009, Nature.

[10]  C. Sander,et al.  Genome-wide identification of microRNA targets in human ES cells reveals a role for miR-302 in modulating BMP response. , 2011, Genes & development.

[11]  Henry Adams,et al.  REST maintains self-renewal and pluripotency of embryonic stem cells , 2008, Nature.

[12]  Gonçalo Castelo-Branco,et al.  Nanog Overcomes Reprogramming Barriers and Induces Pluripotency in Minimal Conditions , 2011, Current Biology.

[13]  Joel S Parker,et al.  Extensive post-transcriptional regulation of microRNAs and its implications for cancer. , 2006, Genes & development.

[14]  G. Daley,et al.  Selective Blockade of MicroRNA Processing by Lin28 , 2008, Science.

[15]  B. Doble,et al.  The ground state of embryonic stem cell self-renewal , 2008, Nature.

[16]  M. Trotter,et al.  Derivation of pluripotent epiblast stem cells from mammalian embryos , 2007, Nature.

[17]  Yoshifumi Kawamura,et al.  Direct reprogramming of somatic cells is promoted by maternal transcription factor Glis1 , 2011, Nature.

[18]  J. Miyazaki,et al.  Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells , 2000, Nature Genetics.

[19]  J. Nichols,et al.  BMP Induction of Id Proteins Suppresses Differentiation and Sustains Embryonic Stem Cell Self-Renewal in Collaboration with STAT3 , 2003, Cell.

[20]  C. Mayr,et al.  Widespread Shortening of 3′UTRs by Alternative Cleavage and Polyadenylation Activates Oncogenes in Cancer Cells , 2009, Cell.

[21]  L. Smirnova,et al.  A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment , 2008, Nature Cell Biology.

[22]  H. Horvitz,et al.  Heterochronic mutants of the nematode Caenorhabditis elegans. , 1984, Science.

[23]  D. Bartel,et al.  Intronic microRNA precursors that bypass Drosha processing , 2007, Nature.

[24]  P. Sharp,et al.  Mir-290–295 deficiency in mice results in partially penetrant embryonic lethality and germ cell defects , 2011, Proceedings of the National Academy of Sciences.

[25]  Robert L. Judson,et al.  Embryonic stem cell–specific microRNAs promote induced pluripotency , 2009, Nature Biotechnology.

[26]  G. Pan,et al.  MicroRNA-145 Regulates OCT4, SOX2, and KLF4 and Represses Pluripotency in Human Embryonic Stem Cells , 2009, Cell.

[27]  Megan F. Cole,et al.  Connecting microRNA Genes to the Core Transcriptional Regulatory Circuitry of Embryonic Stem Cells , 2008, Cell.

[28]  Manfred Kunz,et al.  MicroRNA let-7b targets important cell cycle molecules in malignant melanoma cells and interferes with anchorage-independent growth , 2008, Cell Research.

[29]  K. Hochedlinger,et al.  Tgfβ Signal Inhibition Cooperates in the Induction of iPSCs and Replaces Sox2 and cMyc , 2009, Current Biology.

[30]  Yuriy L Orlov,et al.  The nuclear receptor Nr5a2 can replace Oct4 in the reprogramming of murine somatic cells to pluripotent cells. , 2010, Cell stem cell.

[31]  Lin He,et al.  MicroRNAs: small RNAs with a big role in gene regulation , 2004, Nature Reviews Genetics.

[32]  Byoung-Tak Zhang,et al.  Molecular Basis for the Recognition of Primary microRNAs by the Drosha-DGCR8 Complex , 2006, Cell.

[33]  E. Lai,et al.  The Mirtron Pathway Generates microRNA-Class Regulatory RNAs in Drosophila , 2007, Cell.

[34]  Shulan Tian,et al.  Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells , 2007, Science.

[35]  Yuriy L. Orlov,et al.  Tbx3 improves the germ-line competency of induced pluripotent stem cells , 2010, Nature.

[36]  A. Smith,et al.  Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. , 1998, Genes & development.

[37]  Austin G Smith,et al.  FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment , 2007, Development.

[38]  Rudolf Jaenisch,et al.  Reprogramming factor stoichiometry influences the epigenetic state and biological properties of induced pluripotent stem cells. , 2011, Cell stem cell.

[39]  C. Joo,et al.  Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. , 2008, Molecular cell.

[40]  T. Ichisaka,et al.  Suppression of induced pluripotent stem cell generation by the p53–p21 pathway , 2009, Nature.

[41]  Mudit Gupta,et al.  Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. , 2011, Cell stem cell.

[42]  Rudolf Jaenisch,et al.  DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal , 2007, Nature Genetics.

[43]  J. M. Thomson,et al.  Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing. , 2008, RNA.

[44]  Shridar Ganesan,et al.  Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. , 2005, Genes & development.

[45]  M. Kaufman,et al.  Establishment in culture of pluripotential cells from mouse embryos , 1981, Nature.

[46]  H. Niwa,et al.  Synergistic action of Wnt and LIF in maintaining pluripotency of mouse ES cells. , 2006, Biochemical and biophysical research communications.

[47]  R. Shiekhattar,et al.  TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing , 2005, Nature.

[48]  David W. Taylor,et al.  A Novel miRNA Processing Pathway Independent of Dicer Requires Argonaute2 Catalytic Activity , 2010, Science.

[49]  Tomohiro Kono,et al.  Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells , 2010, Nature.

[50]  Robert L. Judson,et al.  Opposing microRNA families regulate self-renewal in mouse embryonic stem cells , 2010, Nature.

[51]  Robert Blelloch,et al.  Mouse ES cells express endogenous shRNAs, siRNAs, and other Microprocessor-independent, Dicer-dependent small RNAs. , 2008, Genes & development.

[52]  M. Zavolan,et al.  MicroRNAs control de novo DNA methylation through regulation of transcriptional repressors in mouse embryonic stem cells , 2008, Nature Structural &Molecular Biology.

[53]  E. Lai,et al.  MicroRNA biogenesis via splicing and exosome-mediated trimming in Drosophila. , 2010, Molecular cell.

[54]  P. Sharp,et al.  Embryonic stem cell-specific MicroRNAs. , 2003, Developmental cell.

[55]  Megan F. Cole,et al.  Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells , 2005, Cell.

[56]  Lin Zhang,et al.  Identification of MicroRNAs Regulating Reprogramming Factor LIN28 in Embryonic Stem Cells and Cancer Cells* , 2010, The Journal of Biological Chemistry.

[57]  J. Roder,et al.  Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[58]  Kevin J Luebke,et al.  Faculty Opinions recommendation of The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs. , 2009 .

[59]  Zhonghan Li,et al.  Small RNA-mediated regulation of iPS cell generation , 2011, The EMBO journal.

[60]  Michael F. Lin,et al.  Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals , 2009, Nature.

[61]  John K. Heath,et al.  Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides , 1988, Nature.

[62]  Oliver H. Tam,et al.  Characterization of Dicer-deficient murine embryonic stem cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[63]  J. Rinn,et al.  lincRNAs act in the circuitry controlling pluripotency and differentiation , 2011, Nature.

[64]  G. Martin,et al.  Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[65]  V. Kim,et al.  Biogenesis of small RNAs in animals , 2009, Nature Reviews Molecular Cell Biology.

[66]  J. Wrana,et al.  Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. , 2010, Cell stem cell.

[67]  Hideyuki Okano,et al.  Musashi1 Cooperates in Abnormal Cell Lineage Protein 28 (Lin28)-mediated Let-7 Family MicroRNA Biogenesis in Early Neural Differentiation*♦ , 2011, The Journal of Biological Chemistry.

[68]  R. Young,et al.  Stem Cells, the Molecular Circuitry of Pluripotency and Nuclear Reprogramming , 2008, Cell.

[69]  Hitoshi Niwa,et al.  A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells , 2009, Nature.

[70]  Robert Blelloch,et al.  Embryonic Stem Cell Specific MicroRNAs Regulate the G1/S Transition and Promote Rapid Proliferation , 2008, Nature Genetics.

[71]  V. Ambros,et al.  The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 , 1993, Cell.

[72]  Dimitrios Iliopoulos,et al.  Lin28A and Lin28B Inhibit let-7 MicroRNA Biogenesis by Distinct Mechanisms , 2011, Cell.

[73]  G. Hannon,et al.  A dicer-independent miRNA biogenesis pathway that requires Ago catalysis , 2010, Nature.

[74]  A. Pantazi,et al.  Members of the miR-290 cluster modulate in vitro differentiation of mouse embryonic stem cells. , 2009, Differentiation; research in biological diversity.

[75]  R. McKay,et al.  New cell lines from mouse epiblast share defining features with human embryonic stem cells , 2007, Nature.

[76]  Jialiang Liang,et al.  A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. , 2010, Cell stem cell.

[77]  Alessandro Rosa,et al.  A regulatory circuitry comprised of miR‐302 and the transcription factors OCT4 and NR2F2 regulates human embryonic stem cell differentiation , 2011, The EMBO journal.

[78]  Yong Jin Choi,et al.  miR-34 miRNAs provide a barrier for somatic cell reprogramming , 2011, Nature Cell Biology.

[79]  A. Bradley,et al.  Formation of germ-line chimaeras from embryo-derived teratocarcinoma cell lines , 1984, Nature.

[80]  Mitsugu Sekimoto,et al.  Reprogramming of mouse and human cells to pluripotency using mature microRNAs. , 2011, Cell stem cell.

[81]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.