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

  • 5,706
    views
  • 1,129
    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. Chromosomes and Gene Expression
    2. Genetics and Genomics

    Evolutionary adaptation of an HP1-protein chromodomain integrates chromatin and DNA sequence signals

    Lisa Baumgartner, Jonathan J Ipsaro ... Julius Brennecke
    Research Advance

    Members of the diverse heterochromatin protein 1 (HP1) family play crucial roles in heterochromatin formation and maintenance. Despite the similar affinities of their chromodomains for di- and tri-methylated histone H3 lysine 9 (H3K9me2/3), different HP1 proteins exhibit distinct chromatin-binding patterns, likely due to interactions with various specificity factors. Previously, we showed that the chromatin-binding pattern of the HP1 protein Rhino, a crucial factor of the Drosophila PIWI-interacting RNA (piRNA) pathway, is largely defined by a DNA sequence-specific C2H2 zinc finger protein named Kipferl (Baumgartner et al., 2022). Here, we elucidate the molecular basis of the interaction between Rhino and its guidance factor Kipferl. Through phylogenetic analyses, structure prediction, and in vivo genetics, we identify a single amino acid change within Rhino’s chromodomain, G31D, that does not affect H3K9me2/3 binding but disrupts the interaction between Rhino and Kipferl. Flies carrying the rhinoG31D mutation phenocopy kipferl mutant flies, with Rhino redistributing from piRNA clusters to satellite repeats, causing pronounced changes in the ovarian piRNA profile of rhinoG31D flies. Thus, Rhino’s chromodomain functions as a dual-specificity module, facilitating interactions with both a histone mark and a DNA-binding protein.

    1. Biochemistry and Chemical Biology
    2. Chromosomes and Gene Expression

    Human DDX6 regulates translation and decay of inefficiently translated mRNAs

    Ramona Weber, Chung-Te Chang
    Research Article

    Recent findings indicate that the translation elongation rate influences mRNA stability. One of the factors that has been implicated in this link between mRNA decay and translation speed is the yeast DEAD-box helicase Dhh1p. Here, we demonstrated that the human ortholog of Dhh1p, DDX6, triggers the deadenylation-dependent decay of inefficiently translated mRNAs in human cells. DDX6 interacts with the ribosome through the Phe-Asp-Phe (FDF) motif in its RecA2 domain. Furthermore, RecA2-mediated interactions and ATPase activity are both required for DDX6 to destabilize inefficiently translated mRNAs. Using ribosome profiling and RNA sequencing, we identified two classes of endogenous mRNAs that are regulated in a DDX6-dependent manner. The identified targets are either translationally regulated or regulated at the steady-state-level and either exhibit signatures of poor overall translation or of locally reduced ribosome translocation rates. Transferring the identified sequence stretches into a reporter mRNA caused translation- and DDX6-dependent degradation of the reporter mRNA. In summary, these results identify DDX6 as a crucial regulator of mRNA translation and decay triggered by slow ribosome movement and provide insights into the mechanism by which DDX6 destabilizes inefficiently translated mRNAs.