Reciprocal actions of REST and a microRNA promote neuronal identity

MicroRNAs (miRNAs) are implicated in both tissue differentiation and maintenance of tissue identity. In most cases, however, the mechanisms underlying their regulation are not known. One brain-specific miRNA, miR-124a, decreases the levels of hundreds of nonneuronal transcripts, such that its introduction into HeLa cells promotes a neuronal-like mRNA profile. The transcriptional repressor, RE1 silencing transcription factor (REST), has a reciprocal activity, inhibiting the expression of neuronal genes in nonneuronal cells. Here, we show that REST regulates the expression of a family of miRNAs, including brain-specific miR-124a. In nonneuronal cells and neural progenitors, REST inhibits miR-124a expression, allowing the persistence of nonneuronal transcripts. As progenitors differentiate into mature neurons, REST leaves miR-124a gene loci, and nonneuronal transcripts are degraded selectively. Thus, the combined transcriptional and posttranscriptional consequences of REST action maximize the contrast between neuronal and nonneuronal cell phenotypes.

[1]  H. Horvitz,et al.  The let-7 MicroRNA family members mir-48, mir-84, and mir-241 function together to regulate developmental timing in Caenorhabditis elegans. , 2005, Developmental cell.

[2]  J. Morris,et al.  REST-VP16 activates multiple neuronal differentiation genes in human NT2 cells. , 2000, Nucleic acids research.

[3]  E. J. Simon,et al.  Identification of a neurorestrictive suppressor element (NRSE) in the human mu-opioid receptor gene. , 2001, Brain research. Molecular brain research.

[4]  J. Changeux,et al.  The neuron-restrictive silencer element: a dual enhancer/silencer crucial for patterned expression of a nicotinic receptor gene in the brain. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Gail Mandel,et al.  REST: A mammalian silencer protein that restricts sodium channel gene expression to neurons , 1995, Cell.

[6]  A. Roopra,et al.  Transcriptional Repression by Neuron-Restrictive Silencer Factor Is Mediated via the Sin3-Histone Deacetylase Complex , 2000, Molecular and Cellular Biology.

[7]  J. Majzoub,et al.  Repressor Element Silencing Transcription Factor/Neuron-restrictive Silencing Factor (REST/NRSF) Can Act as an Enhancer as Well as a Repressor of Corticotropin-releasing Hormone Gene Transcription* , 2001, The Journal of Biological Chemistry.

[8]  Oliver Hobert,et al.  A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans , 2003, Nature.

[9]  Gail Mandel,et al.  Defining the CREB Regulon A Genome-Wide Analysis of Transcription Factor Regulatory Regions , 2004, Cell.

[10]  Andrew R. Bassett,et al.  A Conserved Role But Different Partners for the Transcriptional Corepressor CoREST in Fly and Mammalian Nervous System Formation , 2004, The Journal of Neuroscience.

[11]  David J. Anderson,et al.  Cell Type-specific Regulation of Choline Acetyltransferase Gene Expression , 1996, The Journal of Biological Chemistry.

[12]  G. Edelman,et al.  Tissue-specific Expression of the L1 Cell Adhesion Molecule Is Modulated by the Neural Restrictive Silencer Element , 1997, The Journal of cell biology.

[13]  H. Sambrook.  Molecular cloning : a laboratory manual. Cold Spring Harbor, NY , 1989 .

[14]  Sing-Hoi Sze,et al.  Corepressor-Dependent Silencing of Chromosomal Regions Encoding Neuronal Genes , 2002, Science.

[15]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[16]  T. Tuschl,et al.  Identification of Tissue-Specific MicroRNAs from Mouse , 2002, Current Biology.

[17]  Debora S. Marks,et al.  Antisense-Mediated Depletion Reveals Essential and Specific Functions of MicroRNAs in Drosophila Development , 2005, Cell.

[18]  Berthold Göttgens,et al.  Genome-wide analysis of repressor element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) target genes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Konstantin Khrapko,et al.  A microRNA array reveals extensive regulation of microRNAs during brain development. , 2003, RNA.

[20]  Oliver Hobert,et al.  MicroRNAs act sequentially and asymmetrically to control chemosensory laterality in the nematode , 2004, Nature.

[21]  V. Kim.  MicroRNA biogenesis: coordinated cropping and dicing , 2005, Nature Reviews Molecular Cell Biology.

[22]  T. Haga,et al.  Expression of the Rat m4 Muscarinic Acetylcholine Receptor Gene Is Regulated by the Neuron-restrictive Silencer Element/Repressor Element 1* , 1997, The Journal of Biological Chemistry.

[23]  Yong Zhao,et al.  Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis , 2005, Nature.

[24]  Olga Varlamova,et al.  A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[25]  D J Anderson,et al.  The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes , 1995, Science.

[26]  J. Castle,et al.  Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs , 2005, Nature.

[27]  Ravi Jain,et al.  MicroRNA-143 Regulates Adipocyte Differentiation* , 2004, Journal of Biological Chemistry.

[28]  J. Kusiak,et al.  Single-stranded DNA-binding Proteins and Neuron-restrictive Silencer Factor Participate in Cell-specific Transcriptional Control of the NMDAR1 Gene* , 1998, The Journal of Biological Chemistry.

[29]  V. Ambros,et al.  The Cold Shock Domain Protein LIN-28 Controls Developmental Timing in C. elegans and Is Regulated by the lin-4 RNA , 1997, Cell.

[30]  Lin He,et al.  MicroRNAs: small RNAs with a big role in gene regulation , 2004, Nature reviews genetics.

[31]  D. Wilkin,et al.  Neuron , 2001, Brain Research.

[32]  V. Ambros,et al.  Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation , 2004, Genome Biology.

[33]  Bruce A. Hay,et al.  The Drosophila MicroRNA Mir-14 Suppresses Cell Death and Is Required for Normal Fat Metabolism , 2003, Current Biology.

[34]  G. Ruvkun,et al.  Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans , 1993, Cell.

[35]  M. Hohl,et al.  RE-1 silencing transcription factor (REST) regulates human synaptophysin gene transcription through an intronic sequence-specific DNA-binding site. , 2002, European journal of biochemistry.

[36]  J. Quinn,et al.  Neuron restrictive silencer factor as a modulator of neuropeptide gene expression , 2002, Regulatory Peptides.

[37]  D. Bartel,et al.  MicroRNA-Directed Cleavage of HOXB8 mRNA , 2004, Science.

[38]  R. Russell,et al.  bantam Encodes a Developmentally Regulated microRNA that Controls Cell Proliferation and Regulates the Proapoptotic Gene hid in Drosophila , 2003, Cell.

[39]  G. Mandel,et al.  REST and Its Corepressors Mediate Plasticity of Neuronal Gene Chromatin throughout Neurogenesis , 2005, Cell.

[40]  D. Burt,et al.  Transcriptional regulation of GABAA receptor γ2 subunit gene , 1999 .

[41]  N. Rajewsky,et al.  A pancreatic islet-specific microRNA regulates insulin secretion , 2004, Nature.

[42]  T. Jessell,et al.  Progression from Extrinsic to Intrinsic Signaling in Cell Fate Specification A View from the Nervous System , 1999, Cell.

[43]  Lena Smirnova,et al.  Regulation of miRNA expression during neural cell specification , 2005, The European journal of neuroscience.

[44]  Ali H. Brivanlou,et al.  Neural induction, the default model and embryonic stem cells , 2002, Nature Reviews Neuroscience.

[45]  Anton J. Enright,et al.  Materials and Methods Figs. S1 to S4 Tables S1 to S5 References and Notes Micrornas Regulate Brain Morphogenesis in Zebrafish , 2022 .

[46]  B. Reinhart,et al.  The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans , 2000, Nature.

[47]  T. Moninger,et al.  Incorporation of adenovirus in calcium phosphate precipitates enhances gene transfer to airway epithelia in vitro and in vivo. , 1998, The Journal of clinical investigation.

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

[49]  Thomas Tuschl,et al.  Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing. , 2004, RNA.

[50]  D. Bartel,et al.  MicroRNAs Modulate Hematopoietic Lineage Differentiation , 2004, Science.

[51]  P. Brehm,et al.  Regulation of Neuronal Traits by a Novel Transcriptional Complex , 2001, Neuron.

[52]  M. Rudnicki,et al.  Retinoic acid-induced neural differentiation of embryonal carcinoma cells , 1983, Molecular and cellular biology.

[53]  M. Anderson,et al.  CoREST: a functional corepressor required for regulation of neural-specific gene expression. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[54]  S. Heinemann,et al.  Regulation of GluR2 promoter activity by neurotrophic factors via a neuron‐restrictive silencer element , 2000, The European journal of neuroscience.

[55]  H. Horvitz,et al.  MicroRNA Expression in Zebrafish Embryonic Development , 2005, Science.

[56]  O. Hobert.  Common logic of transcription factor and microRNA action. , 2004, Trends in biochemical sciences.

[57]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[58]  F. Miller,et al.  A Critical Temporal Requirement for the Retinoblastoma Protein Family During Neuronal Determination , 1998, The Journal of cell biology.

[59]  Gary Ruvkun,et al.  Identification of many microRNAs that copurify with polyribosomes in mammalian neurons , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[60]  E. Miska,et al.  The Co-repressor mSin3A Is a Functional Component of the REST-CoREST Repressor Complex* , 2000, The Journal of Biological Chemistry.

[61]  L. Chin,et al.  A Genetic Screen for Candidate Tumor Suppressors Identifies REST , 2005, Cell.

[62]  C. Becker,et al.  Reduced expression of the neuron restrictive silencer factor permits transcription of glycine receptor α1 subunit in small-cell lung cancer cells , 2003, Oncogene.