Reciprocal Actions of REST and a MicroRNA Promote Neuronal Identity

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2006 Feb 8

PMID 16461918

Citations 375

Authors

Cecilia Conaco

Stefanie Otto

Jong-Jin Han

Gail Mandel

Affiliations

Soon will be listed here.

Abstract

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.

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References

Roopra A, Sharling L, Wood I, Briggs T, Bachfischer U, Paquette A . Transcriptional repression by neuron-restrictive silencer factor is mediated via the Sin3-histone deacetylase complex. Mol Cell Biol. 2000; 20(6):2147-57. PMC: 110831. DOI: 10.1128/MCB.20.6.2147-2157.2000. View

Yekta S, Shih I, Bartel D . MicroRNA-directed cleavage of HOXB8 mRNA. Science. 2004; 304(5670):594-6. DOI: 10.1126/science.1097434. View

Grimes J, Nielsen S, Battaglioli E, Miska E, Speh J, Berry D . The co-repressor mSin3A is a functional component of the REST-CoREST repressor complex. J Biol Chem. 2000; 275(13):9461-7. DOI: 10.1074/jbc.275.13.9461. View

Brene S, Messer C, Okado H, Hartley M, Heinemann S, Nestler E . Regulation of GluR2 promoter activity by neurotrophic factors via a neuron-restrictive silencer element. Eur J Neurosci. 2000; 12(5):1525-33. DOI: 10.1046/j.1460-9568.2000.00040.x. View

Immaneni A, Lawinger P, Zhao Z, Lu W, Rastelli L, Morris J . REST-VP16 activates multiple neuronal differentiation genes in human NT2 cells. Nucleic Acids Res. 2000; 28(17):3403-10. PMC: 110685. DOI: 10.1093/nar/28.17.3403. View

Seth K, Majzoub J . 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. J Biol Chem. 2001; 276(17):13917-23. DOI: 10.1074/jbc.M007745200. View

Andria M, Simon E . Identification of a neurorestrictive suppressor element (NRSE) in the human mu-opioid receptor gene. Brain Res Mol Brain Res. 2001; 91(1-2):73-80. DOI: 10.1016/s0169-328x(01)00124-3. View

Ballas N, Battaglioli E, Atouf F, Andres M, Chenoweth J, Anderson M . Regulation of neuronal traits by a novel transcriptional complex. Neuron. 2001; 31(3):353-65. DOI: 10.1016/s0896-6273(01)00371-3. View

Munoz-Sanjuan I, Brivanlou A . Neural induction, the default model and embryonic stem cells. Nat Rev Neurosci. 2002; 3(4):271-80. DOI: 10.1038/nrn786. View

10.

Wightman B, Ha I, Ruvkun G . Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell. 1993; 75(5):855-62. DOI: 10.1016/0092-8674(93)90530-4. View

11.

Schoenherr C, Anderson D . The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes. Science. 1995; 267(5202):1360-3. DOI: 10.1126/science.7871435. View

12.

Chong J, Tapia-Ramirez J, Kim S, Toledo-Aral J, Zheng Y, Boutros M . REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell. 1995; 80(6):949-57. DOI: 10.1016/0092-8674(95)90298-8. View

13.

Lonnerberg P, Schoenherr C, Anderson D, Ibanez C . Cell type-specific regulation of choline acetyltransferase gene expression. Role of the neuron-restrictive silencer element and cholinergic-specific enhancer sequences. J Biol Chem. 1996; 271(52):33358-65. DOI: 10.1074/jbc.271.52.33358. View

14.

Mieda M, Haga T, Saffen D . Expression of the rat m4 muscarinic acetylcholine receptor gene is regulated by the neuron-restrictive silencer element/repressor element 1. J Biol Chem. 1997; 272(9):5854-60. DOI: 10.1074/jbc.272.9.5854. View

15.

Moss E, Lee R, Ambros V . The cold shock domain protein LIN-28 controls developmental timing in C. elegans and is regulated by the lin-4 RNA. Cell. 1997; 88(5):637-46. DOI: 10.1016/s0092-8674(00)81906-6. View

16.

BESSIS A, Champtiaux N, Chatelin L, Changeux J . The neuron-restrictive silencer element: a dual enhancer/silencer crucial for patterned expression of a nicotinic receptor gene in the brain. Proc Natl Acad Sci U S A. 1997; 94(11):5906-11. PMC: 20879. DOI: 10.1073/pnas.94.11.5906. View

17.

Kallunki P, Edelman G, Jones F . Tissue-specific expression of the L1 cell adhesion molecule is modulated by the neural restrictive silencer element. J Cell Biol. 1997; 138(6):1343-54. PMC: 2132545. DOI: 10.1083/jcb.138.6.1343. View

18.

Bai G, Norton D, Prenger M, Kusiak J . Single-stranded DNA-binding proteins and neuron-restrictive silencer factor participate in cell-specific transcriptional control of the NMDAR1 gene. J Biol Chem. 1998; 273(2):1086-91. DOI: 10.1074/jbc.273.2.1086. View

19.

Slack R, Wong J, Belliveau D, Miller F . A critical temporal requirement for the retinoblastoma protein family during neuronal determination. J Cell Biol. 1998; 140(6):1497-509. PMC: 2132670. DOI: 10.1083/jcb.140.6.1497. View

20.

Fasbender A, Lee J, Walters R, Moninger T, Zabner J, Welsh M . Incorporation of adenovirus in calcium phosphate precipitates enhances gene transfer to airway epithelia in vitro and in vivo. J Clin Invest. 1998; 102(1):184-93. PMC: 509080. DOI: 10.1172/JCI2732. View