Polycomb and REST-associated histone deacetylases are independent pathways toward a mature neuronal phenotype

  1. James C McGann  Is a corresponding author
  2. Jon A Oyer
  3. Saurabh Garg
  4. Huilan Yao
  5. Jun Liu
  6. Xin Feng
  7. Lujian Liao
  8. John R Yates
  9. Gail Mandel
  1. Oregon Health and Science University, United States
  2. Robert H. Lurie Comprehensive Cancer Center, Feinberg School Of Medicine, United States
  3. Indiana University, United States
  4. Baylor College of Medicine, United States
  5. School of Life Sciences, East China Normal University, China
  6. The Scripps Research Institute, United States

Abstract

The bivalent hypothesis posits that genes encoding developmentalregulators required for early lineage decisions are poised in stem/progenitor cells by the balance between a repressor histone modification (H3K27me3), mediated by the Polycomb Repressor Complex 2 (PRC2), and an activator modification (H3K4me3). Here, we test whether this mechanism applies equally to genes that are not required until terminal differentiation. We focus on the RE1 Silencing Transcription Factor (REST) because it is expressed highly in stem cells, and is an established global repressor of terminal neuronal genes. Elucidation of the REST complex, and comparison of chromatin marks and gene expression levels in control and REST-deficient stem cells, shows that REST target genes are poised by a mechanism independent of Polycomb, even at promoters which bear the H3K27me3 mark. Specifically, genes under REST control are actively repressed in stem cells by a balance of the H3K4me3 mark and a repressor complex that relies on histone deacetylase activity. Thus, chromatin distinctions between pro-neural and terminal neuronal genes are established at the embryonic stem cell stage by two parallel, but distinct, repressor pathways.

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Author details

  1. James C McGann

    Oregon Health and Science University, Portland, United States
    For correspondence
    mcgann@ohsu.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Jon A Oyer

    Robert H. Lurie Comprehensive Cancer Center, Feinberg School Of Medicine, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Saurabh Garg

    Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Huilan Yao

    Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jun Liu

    Indiana University, Bloomington, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Xin Feng

    Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Lujian Liao

    School of Life Sciences, East China Normal University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  8. John R Yates

    The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Gail Mandel

    Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.

Copyright

© 2014, McGann et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. James C McGann
  2. Jon A Oyer
  3. Saurabh Garg
  4. Huilan Yao
  5. Jun Liu
  6. Xin Feng
  7. Lujian Liao
  8. John R Yates
  9. Gail Mandel
(2014)
Polycomb and REST-associated histone deacetylases are independent pathways toward a mature neuronal phenotype
eLife 3:e04235.
https://doi.org/10.7554/eLife.04235

Share this article

https://doi.org/10.7554/eLife.04235

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