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

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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 factors and pathways underlies the importance of safeguarding the genome through multiple means.

DOI: http://dx.doi.org/10.7554/eLife.21666.001

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Most cited references 78

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Identifying ChIP-seq enrichment using MACS.

Jianxing Feng, Tao Liu, Bo Qin … (2012)

Model-based analysis of ChIP-seq (MACS) is a computational algorithm that identifies genome-wide locations of transcription/chromatin factor binding or histone modification from ChIP-seq data. MACS consists of four steps: removing redundant reads, adjusting read position, calculating peak enrichment and estimating the empirical false discovery rate (FDR). In this protocol, we provide a detailed demonstration of how to install MACS and how to use it to analyze three common types of ChIP-seq data sets with different characteristics: the sequence-specific transcription factor FoxA1, the histone modification mark H3K4me3 with sharp enrichment and the H3K36me3 mark with broad enrichment. We also explain how to interpret and visualize the results of MACS analyses. The algorithm requires ∼3 GB of RAM and 1.5 h of computing time to analyze a ChIP-seq data set containing 30 million reads, an estimate that increases with sequence coverage. MACS is open source and is available from http://liulab.dfci.harvard.edu/MACS/.

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RNA-mediated epigenetic regulation of gene expression.

Daniel Holoch, Danesh Moazed (2015)

Diverse classes of RNA, ranging from small to long non-coding RNAs, have emerged as key regulators of gene expression, genome stability and defence against foreign genetic elements. Small RNAs modify chromatin structure and silence transcription by guiding Argonaute-containing complexes to complementary nascent RNA scaffolds and then mediating the recruitment of histone and DNA methyltransferases. In addition, recent advances suggest that chromatin-associated long non-coding RNA scaffolds also recruit chromatin-modifying complexes independently of small RNAs. These co-transcriptional silencing mechanisms form powerful RNA surveillance systems that detect and silence inappropriate transcription events, and provide a memory of these events via self-reinforcing epigenetic loops.

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The Dfam database of repetitive DNA families

Robert Hubley, Robert D. Finn, Jody Clements … (2015)

Repetitive DNA, especially that due to transposable elements (TEs), makes up a large fraction of many genomes. Dfam is an open access database of families of repetitive DNA elements, in which each family is represented by a multiple sequence alignment and a profile hidden Markov model (HMM). The initial release of Dfam, featured in the 2013 NAR Database Issue, contained 1143 families of repetitive elements found in humans, and was used to produce more than 100 Mb of additional annotation of TE-derived regions in the human genome, with improved speed. Here, we describe recent advances, most notably expansion to 4150 total families including a comprehensive set of known repeat families from four new organisms (mouse, zebrafish, fly and nematode). We describe improvements to coverage, and to our methods for identifying and reducing false annotation. We also describe updates to the website interface. The Dfam website has moved to http://dfam.org. Seed alignments, profile HMMs, hit lists and other underlying data are available for download.

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Author and article information

Contributors

Edith Heard: Role: Reviewing editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (hwp): eLife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 15 March 2017

Publication date Collection: 2017

Volume: 6

Electronic Location Identifier: e21666

Affiliations

[1]deptThe Gurdon Institute and Department of Genetics , University of Cambridge , Cambridge, United Kingdom

Institut Curie , France

Author notes

ja219@ 123456cam.ac.uk

[†]

These authors contributed equally to this work.

Author information

Alicia N McMurchy http://orcid.org/0000-0002-7033-8790

Przemyslaw Stempor http://orcid.org/0000-0002-9464-7475

Ni Huang http://orcid.org/0000-0001-8849-038X

Eric A Miska http://orcid.org/0000-0002-4450-576X

Julie Ahringer http://orcid.org/0000-0002-7074-4051

Article

Publisher ID: 21666

DOI: 10.7554/eLife.21666

PMC ID: 5395297

PubMed ID: 28294943

SO-VID: 06a178f9-0ff9-4222-bd78-550d3b552a74

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This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 20 September 2016

Date accepted : 10 March 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100010269, Wellcome;

Award ID: 054523

Award Recipient : Julie Ahringer

Funded by: FundRef http://dx.doi.org/10.13039/100010269, Wellcome;

Award ID: 101863

Award Recipient : Julie Ahringer

Funded by: FundRef http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;

Award Recipient : Alicia N McMurchy

Funded by: FundRef http://dx.doi.org/10.13039/501100000289, Cancer Research UK;

Award ID: C13474/A18583

Award Recipient : Eric A Miska

Funded by: FundRef http://dx.doi.org/10.13039/501100000854, Human Frontier Science Program;

Award Recipient : Alexandra Sapetschnig

Funded by: FundRef http://dx.doi.org/10.13039/100010269, Wellcome;

Award ID: 104640/Z/14/Z

Award Recipient : Eric A Miska

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

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Author impact statement Genome-wide profiling and functional analyses reveal a network of heterochromatin and small RNA factors that silences repetitive elements and prevents genotoxic stress to ensure fertility.

ScienceOpen disciplines: Life sciences

Keywords: heterochromatin,germ line,repetitive elements,dna damage,nuclear rnai,pirna,c. elegans

Data availability:

ScienceOpen disciplines: Life sciences

Keywords: heterochromatin, germ line, repetitive elements, dna damage, nuclear rnai, pirna, c. elegans

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

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Genome Integrity

Most cited references 78

Identifying ChIP-seq enrichment using MACS.

RNA-mediated epigenetic regulation of gene expression.

The Dfam database of repetitive DNA families

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