A team of heterochromatin factors collaborates with small RNA pathways to combat repetitive elements and germline stress
- University of Cambridge, United Kingdom
- The Gurdon Institute, United Kingdom
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
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A team of heterochromatin factors collaborates with small RNA pathways to combat repetitive elements and germline stressPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE87524).
Article and author information
Author details
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.
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.
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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
Further reading
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- Chromosomes and Gene Expression
- Computational and Systems Biology
Genes are often regulated by multiple enhancers. It is poorly understood how the individual enhancer activities are combined to control promoter activity. Anecdotal evidence has shown that enhancers can combine sub-additively, additively, synergistically, or redundantly. However, it is not clear which of these modes are more frequent in mammalian genomes. Here, we systematically tested how pairs of enhancers activate promoters using a three-way combinatorial reporter assay in mouse embryonic stem cells. By assaying about 69,000 enhancer-enhancer-promoter combinations we found that enhancer pairs generally combine near-additively. This behaviour was conserved across seven developmental promoters tested. Surprisingly, these promoters scale the enhancer signals in a non-linear manner that depends on promoter strength. A housekeeping promoter showed an overall different response to enhancer pairs, and a smaller dynamic range. Thus, our data indicate that enhancers mostly act additively, but promoters transform their collective effect non-linearly.
