1. Developmental Biology
  2. Chromosomes and Gene Expression
Download icon

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
Research Article
  • Cited 27
  • Views 2,934
  • Annotations
Cite this article as: eLife 2014;3:e04235 doi: 10.7554/eLife.04235

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.

Article and author information

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.

Reviewing Editor

  1. Danny Reinberg, Howard Hughes Medical Institute, New York University School of Medicine, United States

Publication history

  1. Received: August 2, 2014
  2. Accepted: September 22, 2014
  3. Accepted Manuscript published: September 24, 2014 (version 1)
  4. Version of Record published: October 20, 2014 (version 2)

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.

Metrics

  • 2,934
    Page views
  • 399
    Downloads
  • 27
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Developmental Biology
    2. Neuroscience
    Laura Morcom et al.
    Research Article Updated

    The forebrain hemispheres are predominantly separated during embryogenesis by the interhemispheric fissure (IHF). Radial astroglia remodel the IHF to form a continuous substrate between the hemispheres for midline crossing of the corpus callosum (CC) and hippocampal commissure (HC). Deleted in colorectal carcinoma (DCC) and netrin 1 (NTN1) are molecules that have an evolutionarily conserved function in commissural axon guidance. The CC and HC are absent in Dcc and Ntn1 knockout mice, while other commissures are only partially affected, suggesting an additional aetiology in forebrain commissure formation. Here, we find that these molecules play a critical role in regulating astroglial development and IHF remodelling during CC and HC formation. Human subjects with DCC mutations display disrupted IHF remodelling associated with CC and HC malformations. Thus, axon guidance molecules such as DCC and NTN1 first regulate the formation of a midline substrate for dorsal commissures prior to their role in regulating axonal growth and guidance across it.

    1. Developmental Biology
    2. Immunology and Inflammation
    Lydia K Lutes et al.
    Research Article Updated

    Functional tuning of T cells based on their degree of self-reactivity is established during positive selection in the thymus, although how positive selection differs for thymocytes with relatively low versus high self-reactivity is unclear. In addition, preselection thymocytes are highly sensitive to low-affinity ligands, but the mechanism underlying their enhanced T cell receptor (TCR) sensitivity is not fully understood. Here we show that murine thymocytes with low self-reactivity experience briefer TCR signals and complete positive selection more slowly than those with high self-reactivity. Additionally, we provide evidence that cells with low self-reactivity retain a preselection gene expression signature as they mature, including genes previously implicated in modulating TCR sensitivity and a novel group of ion channel genes. Our results imply that thymocytes with low self-reactivity downregulate TCR sensitivity more slowly during positive selection, and associate membrane ion channel expression with thymocyte self-reactivity and progress through positive selection.