Sequence features of retrotransposons allow for epigenetic variability
- Beckman Research Institute, United States
- Van Andel Research Institute, United States
Abstract
Transposable elements (TEs) are mobile genetic elements that make up a large fraction of mammalian genomes. While select TEs have been co-opted in host genomes to have function, the majority of these elements are epigenetically silenced by DNA methylation in somatic cells. However, some TEs in mice, including the Intracisternal A-particle (IAP) subfamily of retrotransposons, have been shown to display interindividual variation in DNA methylation. Recent work has revealed that IAP sequence differences and strain-specific KRAB zinc finger proteins (KZFPs) may influence the methylation state of these IAPs. However, the mechanisms underlying the establishment and maintenance of interindividual variability in DNA methylation still remain unclear. Here we report that sequence content and genomic context influence the likelihood that IAPs become variably methylated. IAPs that differ from consensus IAP sequences have altered KZFP recruitment that can lead to decreased KAP1 recruitment when in proximity of constitutively expressed genes. These variably methylated loci have a high CpG density, similar to CpG islands, and can be bound by ZF-CxxC proteins, providing a potential mechanism to maintain this permissive chromatin environment and protect from DNA methylation. These observations indicate that variably methylated IAPs escape silencing through both attenuation of KZFP binding and recognition by ZF-CxxC proteins to maintain a hypomethylated state.
Data availability
All datasets generated in this study have been submitted to GEO under accession code GSE176176.
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Mechanisms of interindividual epigenetic variability at CpG dense transposable elementsNCBI Gene Expression Omnibus, GSE176176.
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The role of DNMT3A and TET1 in regulating promoter epigenetic landscapesNCBI Gene Expression Omnibus, GSE100957.
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The BLUEPRINT Murine Lymphocyte Epigenome Reference Resource [ChIP-seq]NCBI Gene Expression Omnibus, GSM2480410.
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Genome-wide maps of CFP1, RNA Polymerase II and H3K4me3 in mouse brainNCBI Gene Expression Omnibus, GSE18578.
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Whole genome analysis of the methylome and hydroxymethylome in normal and malignant lung and liverNCBI Gene Expression Omnibus, GSM1716957.
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ChIP-seq analysis of CFP1 and related moleculesNCBI Gene Expression Omnibus, GSM3132538.
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Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic ObesityEuropean Nucleotide Archive, PRJEB11740.
Article and author information
Author details
Funding
National Institutes of Health (R01DK112041)
- Dustin E Schones
National Institutes of Health (R01CA220693)
- Dustin E Schones
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal protocols were in accordance with German and United Kingdom legislation; Project license numbers 80/2098, 80/2497, and 35-9185.81/G-10/94.
Copyright
© 2021, Costello 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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Sequence features of retrotransposons allow for epigenetic variability
eLife 10:e71104.
https://doi.org/10.7554/eLife.71104
Further reading
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O-GlcNAcylation is an essential intracellular protein modification mediated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Recently, missense mutations in OGT have been linked to intellectual disability, indicating that this modification is important for the development and functioning of the nervous system. However, the processes that are most sensitive to perturbations in O-GlcNAcylation remain to be identified. Here, we uncover quantifiable phenotypes in the fruit fly Drosophila melanogaster carrying a patient-derived OGT mutation in the catalytic domain. Hypo-O-GlcNAcylation leads to defects in synaptogenesis and reduced sleep stability. Both these phenotypes can be partially rescued by genetically or chemically targeting OGA, suggesting that a balance of OGT/OGA activity is required for normal neuronal development and function.
