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
- Neuroscience
Pathogenic variants in subunits of RNA polymerase (Pol) III cause a spectrum of Polr3-related neurodegenerative diseases including 4H leukodystrophy. Disease onset occurs from infancy to early adulthood and is associated with a variable range and severity of neurological and non-neurological features. The molecular basis of Polr3-related disease pathogenesis is unknown. We developed a postnatal whole-body mouse model expressing pathogenic Polr3a mutations to examine the molecular mechanisms by which reduced Pol III transcription results primarily in central nervous system phenotypes. Polr3a mutant mice exhibit behavioral deficits, cerebral pathology and exocrine pancreatic atrophy. Transcriptome and immunohistochemistry analyses of cerebra during disease progression show a reduction in most Pol III transcripts, induction of innate immune and integrated stress responses and cell-type-specific gene expression changes reflecting neuron and oligodendrocyte loss and microglial activation. Earlier in the disease when integrated stress and innate immune responses are minimally induced, mature tRNA sequencing revealed a global reduction in tRNA levels and an altered tRNA profile but no changes in other Pol III transcripts. Thus, changes in the size and/or composition of the tRNA pool have a causal role in disease initiation. Our findings reveal different tissue- and brain region-specific sensitivities to a defect in Pol III transcription.
