Sequence features of retrotransposons allow for epigenetic variability

Abstract
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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.

The following data sets were generated

1. Costello KR
2. Leung A
3. Trac C
4. Lee M
5. Basam M
6. Pospisilik JA
7. Schones DE
(2021) Mechanisms of interindividual epigenetic variability at CpG dense transposable elements
NCBI Gene Expression Omnibus, GSE176176.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE176176

The following previously published data sets were used

1. Wolf G
2. de Iaco A
3. Sun MA
4. Bruno M
5. Tinkham M
6. Hoang D
7. Mitra Ap
8. Ralls S
9. Trono D
10. Macfarlan TS
(2019) Retrotransposon reactivation and mobilization upon deletions of megabase-scale KRAB zinc finger gene clusters in mice
NCBI Gene Expression Omnibus, GSE115291.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE115291
1. Gu T
2. Lin X
3. Cullen SM
4. Luo M
5. Jeong M
6. Estecio M
7. Shen J
8. Hardikar S
9. Sun D
10. Su J
11. Rux D
12. Guzman A
13. Lee M
14. Qi LS
15. Chen JJ
16. Kyba M
17. Huang Y
18. Chen T
19. Li W
20. Goodell MA
(2018) The role of DNMT3A and TET1 in regulating promoter epigenetic landscapes
NCBI Gene Expression Omnibus, GSE100957.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE100957
(2017) The BLUEPRINT Murine Lymphocyte Epigenome Reference Resource [ChIP-seq]
NCBI Gene Expression Omnibus, GSM2480410.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE94658
1. Thomson JP
2. Skene PJ
3. Selfridge J
4. Guy J
5. Deaton A
6. Kerr A
7. Webb S
8. Andrews R
9. James KD
10. Turner DJ
11. McLaren S
12. Illingworth RS
13. Bird AP
(2010) Genome-wide maps of CFP1, RNA Polymerase II and H3K4me3 in mouse brain
NCBI Gene Expression Omnibus, GSE18578.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE18578
1. Li X
2. Liu Y
3. Salz T
4. Hansen KD
5. Feinberg A
(2016) Whole genome analysis of the methylome and hydroxymethylome in normal and malignant lung and liver
NCBI Gene Expression Omnibus, GSM1716957.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM1716957
(2018) ChIP-seq analysis of CFP1 and related molecules
NCBI Gene Expression Omnibus, GSM3132538.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE114084
1. Li B
2. Qing T
3. Zhu J
4. Wen Z
5. Yu Y
6. Fukumura R
7. Zheng Y
8. Gondo Y
9. Shi L
(2017) A Comprehensive Mouse Transcriptomic BodyMap across 17 Tissues by RNA-seq
NCBI BioProject, PRJNA375882.

https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJNA375882
1. Dalgaard K
2. Landgraf K
3. Heyne S
4. Lempradl A
5. Longinotto J
6. Gossens K
7. Ruf M
8. Orthofer M
9. Strogantsev R
10. Selvaraj M
11. Lu TT
12. Casas E
13. Teperino R
14. Surani MA
15. Zvetkova I
16. Rimmington D
17. Tung YC
18. Lam B
19. Larder R
20. Yeo GS
21. O'Rahilly S
22. Vavouri T
23. Whitelaw E
24. Penninger JM
25. Jenuwein T
26. Cheung CL
27. Ferguson-Smith AC
28. Coll AP
29. Körner A
30. Pospisilik JA
(2016) Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity
European Nucleotide Archive, PRJEB11740.

https://www.ebi.ac.uk/ena/browser/view/PRJEB11740

Article and author information

Author details

Kevin R Costello

Beckman Research Institute, Duarte, United States

Competing interests
The authors declare that no competing interests exist.
Amy Leung

Beckman Research Institute, Duarte, United States

Competing interests
The authors declare that no competing interests exist.
Candi Trac

Beckman Research Institute, Duarte, United States

Competing interests
The authors declare that no competing interests exist.
Michael Lee

Beckman Research Institute, Duarte, United States

Competing interests
The authors declare that no competing interests exist.
Mudaser Basam

Beckman Research Institute, Duarte, United States

Competing interests
The authors declare that no competing interests exist.
J Andrew Popsilik

Van Andel Research Institute, Grand Rapids, United States

Competing interests
The authors declare that no competing interests exist.
Dustin E Schones

Beckman Research Institute, Duarte, United States

For correspondence
dschones@coh.org

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7692-8583

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

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.