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Reciprocal actions of REST and a microRNA promote neuronal identity

Conaco, Cecilia, Otto, Stefanie, Han, Jong-Jin, Mandel, Gail·2006·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0511041103
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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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Crossref · 10.1073/pnas.0511041103

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  • miR-9-1 and miR-9-3 both have upstream RE1 sequences that can be occupied by REST.

    “miR-9-1 and miR-9-3 both have upstream RE1 sequences that is can be occupied by REST (Conaco et al., 2006; Johnson et al., 2008).”

    From The Bifunctional microRNA miR-9/miR-9* Regulates REST and CoREST and Is Downregulated in Huntington's Disease (2008) · cites this paper as Conaco et al., 2006

    The Results identify miR-9-1 and miR-9-3 among loci near REST-binding sites, and report ChIP evidence that REST occupies RE1 sites associated with the identified miRNA genes (Fig. 1A; page not provided). The text of our copy describes those sites as nearby, but does not establish that the RE1 sequences for both loci are upstream. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • REST silences neuronal gene expression in non-neuronal cells.

    “The transcription factor REST silences neuronal gene expression in non-neuronal cells.”

    From The Bifunctional microRNA miR-9/miR-9* Regulates REST and CoREST and Is Downregulated in Huntington's Disease (2008) · cites this paper as Conaco et al., 2006

  • Once in the nucleus, REST can bind RE1 consensus sequences and recruit co-repressors including mSin3, CoREST, and MeCP2 to inactivate neuron-specific genes.

    “Once in the nucleus, REST can bind RE1 consensus sequences and recruit co-repressors including mSin3, the co-repressor of REST (CoREST, also known as RCOR1) and methyl CpG binding protein 2 (MeCP2) (Andres et al., 1999) to inactivate neuron-specific genes (Zuccato et al., 2003; Conaco et al., 2006).”

    From The Bifunctional microRNA miR-9/miR-9* Regulates REST and CoREST and Is Downregulated in Huntington's Disease (2008) · cites this paper as Conaco et al., 2006

  • REST repressor complex binding to RE1 sequences upstream of miRNA transcripts may alter miRNA expression profiles.

    “Similarly, REST repressor complex binding to RE1 sequences upstream of miRNA transcripts may alter miRNA expression profiles (Conaco et al., 2006; Klein et al., 2007).”

    From The Bifunctional microRNA miR-9/miR-9* Regulates REST and CoREST and Is Downregulated in Huntington's Disease (2008) · cites this paper as Conaco et al., 2006

  • REST interacts with CoREST and other transcriptional repressors to regulate neuronal gene expression and lineage commitment through its direct control of both mRNA and miRNA transcripts.

    “REST interacts with CoREST and other transcriptional repressors to regulate neuronal gene expression and lineage commitment through its direct control of both mRNA and, as shown more recently, miRNA transcripts (Vo et al., 2005; Conaco et al., 2006; Mortazavi et al., 2006 ; Visvanathan et al., 2007).”

    From The Bifunctional microRNA miR-9/miR-9* Regulates REST and CoREST and Is Downregulated in Huntington's Disease (2008) · cites this paper as Conaco et al., 2006

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Research works printed but not linked: 4

  1. [35]Kim, J., Krichevsky, A., Grad, Y., Hayes, G. D., Kosik, K. S., Church, G. M. & Ruvkun, G. (2004) Proc. Natl. Acad. Sci. USA 101, 360-365.
  2. [41]Bruce, A. W., Donaldson, I. J., Wood, I. C., Yerbury, S. A., Sadowski, M. I., Chapman, M., Gottgens, B. & Buckley, N. J. (2004) Proc. Natl. Acad. Sci. USA 101, 10458-10463.
  3. [50]Bessis, A., Champtiaux, N., Chatelin, L. & Changeux, J. (1997) Proc. Natl. Acad. Sci. USA 94, 5906-5911.
  4. [61]Sambrook, J., Fritsch, E. F. & Maniatis, T. (1989) Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Lab. Press, Woodbury, NY), pp. 16.32-16.37.

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Authors
Conaco, C., Otto, S., Han, J.-J., & Mandel, G.
Affiliations
Department of Neurobiology and Behavior, Howard Hughes Medical Institute, State University of New York, Stony Brook, NY 11794
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2006-02-06
Volume
103
Issue
7
Pages
2422-2427
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.0511041103
Cited by
641
References
5
Language
en

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