1. Chromosomes and Gene Expression
  2. Genetics and Genomics

A team of heterochromatin factors collaborates with small RNA pathways to combat repetitive elements and germline stress

  1. Alicia N McMurchy
  2. Przemyslaw Stempor
  3. Tessa Gaarenstroom
  4. Brian Wysolmerski
  5. Yan Dong
  6. Darya Aussianikava
  7. Alex Appert
  8. Ni Huang
  9. Paulina Kolasinska-Zwierz
  10. Alexandra Sapetschnig
  11. Eric A Miska
  12. Julie Ahringer  Is a corresponding author
  1. University of Cambridge, United Kingdom
  2. The Gurdon Institute, United Kingdom
https://doi.org/10.7554/eLife.21666
Share this article
Cite this article
  1. Alicia N McMurchy
  2. Przemyslaw Stempor
  3. Tessa Gaarenstroom
  4. Brian Wysolmerski
  5. Yan Dong
  6. Darya Aussianikava
  7. Alex Appert
  8. Ni Huang
  9. Paulina Kolasinska-Zwierz
  10. Alexandra Sapetschnig
  11. Eric A Miska
  12. Julie Ahringer
(2017)
A team of heterochromatin factors collaborates with small RNA pathways to combat repetitive elements and germline stress
eLife 6:e21666.
https://doi.org/10.7554/eLife.21666
  2. Download BibTeX
  3. Download .RIS

Abstract

Repetitive sequences derived from transposons make up a large fraction of eukaryotic genomes and must be silenced to protect genome integrity. Repetitive elements are often found in heterochromatin; however, the roles and interactions of heterochromatin proteins in repeat regulation are poorly understood. Here we show that a diverse set of C. elegans heterochromatin proteins act together with the piRNA and nuclear RNAi pathways to silence repetitive elements and prevent genotoxic stress in the germ line. Mutants in genes encoding HPL-2/HP1, LIN-13, LIN-61, LET-418/Mi-2, and H3K9me2 histone methyltransferase MET-2/SETDB1 also show functionally redundant sterility, increased germline apoptosis, DNA repair defects, and interactions with small RNA pathways. Remarkably, fertility of heterochromatin mutants could be partially restored by inhibiting cep-1/p53, endogenous meiotic double strand breaks, or the expression of MIRAGE1 DNA transposons. Functional redundancy among these factors and pathways underlies the importance of safeguarding the genome through multiple means.

Data availability

The following data sets were generated

Article and author information

Author details

  1. Alicia N McMurchy

    The Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7033-8790

  2. Przemyslaw Stempor

    The Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.

  3. Tessa Gaarenstroom

    Department of Genetics, The Gurdon Institute, University of Cambridge, United Kingdom
    Competing interests
    No competing interests declared.

  4. Brian Wysolmerski

    The Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.

  5. Yan Dong

    The Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.

  6. Darya Aussianikava

    The Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.

  7. Alex Appert

    The Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.

  8. Ni Huang

    The Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8849-038X

  9. Paulina Kolasinska-Zwierz

    The Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.

  10. Alexandra Sapetschnig

    The Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.

  11. Eric A Miska

    The Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4450-576X

  12. Julie Ahringer

    The Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    ja219@cam.ac.uk
    Competing interests
    Julie Ahringer, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7074-4051

Funding

Wellcome (54523)

  • Julie Ahringer

Wellcome (101863)

  • Julie Ahringer

Canadian Institutes of Health Research

  • Alicia N McMurchy

Cancer Research UK (C13474/A18583)

  • Eric A Miska

Human Frontier Science Program

  • Alexandra Sapetschnig

Wellcome (104640/Z/14/Z)

  • Eric A Miska

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Edith Heard, Institut Curie, France

Version history

  1. Received: September 20, 2016
  2. Accepted: March 10, 2017
  3. Accepted Manuscript published: March 15, 2017 (version 1)
  4. Version of Record published: April 18, 2017 (version 2)
  5. Version of Record updated: October 5, 2017 (version 3)

Copyright

© 2017, McMurchy 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

  • 5,660
    views
  • 1,126
    downloads
  • 75
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  1. Alicia N McMurchy
  2. Przemyslaw Stempor
  3. Tessa Gaarenstroom
  4. Brian Wysolmerski
  5. Yan Dong
  6. Darya Aussianikava
  7. Alex Appert
  8. Ni Huang
  9. Paulina Kolasinska-Zwierz
  10. Alexandra Sapetschnig
  11. Eric A Miska
  12. Julie Ahringer
(2017)
A team of heterochromatin factors collaborates with small RNA pathways to combat repetitive elements and germline stress
eLife 6:e21666.
https://doi.org/10.7554/eLife.21666

Share this article

https://doi.org/10.7554/eLife.21666

Categories and tags

Research organism

Further reading

    1. Cancer Biology
    2. Chromosomes and Gene Expression

    Ribosome subunit attrition and activation of the p53–MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition

    Gregory Caleb Howard, Jing Wang ... William P Tansey
    Research Article

    The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the ‘WIN’ site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small-molecule WINi, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anticancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in human MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anticancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies.

    1. Chromosomes and Gene Expression
    2. Immunology and Inflammation

    Foxp3 depends on Ikaros for control of regulatory T cell gene expression and function

    Rajan M Thomas, Matthew C Pahl ... Andrew D Wells
    Research Article

    Ikaros is a transcriptional factor required for conventional T cell development, differentiation, and anergy. While the related factors Helios and Eos have defined roles in regulatory T cells (Treg), a role for Ikaros has not been established. To determine the function of Ikaros in the Treg lineage, we generated mice with Treg-specific deletion of the Ikaros gene (Ikzf1). We find that Ikaros cooperates with Foxp3 to establish a major portion of the Treg epigenome and transcriptome. Ikaros-deficient Treg exhibit Th1-like gene expression with abnormal production of IL-2, IFNg, TNFa, and factors involved in Wnt and Notch signaling. While Ikzf1-Treg-cko mice do not develop spontaneous autoimmunity, Ikaros-deficient Treg are unable to control conventional T cell-mediated immune pathology in response to TCR and inflammatory stimuli in models of IBD and organ transplantation. These studies establish Ikaros as a core factor required in Treg for tolerance and the control of inflammatory immune responses.