Retrotransposition creates sloping shores: a graded influence of hypomethylated CpG islands on flanking CpG sites
- Fiorella C Grandi1,
- James M Rosser1,
- Simon J Newkirk1,
- Jun Yin1,
- Xiaoling Jiang2,
- Zhuo Xing2,
- Leanne Whitmore1,
- Sanum Bashir3,
- Zoltán Ivics4,
- Zsuzsanna Izsvák3,
- Ping Ye1,
- Yuejin E Yu2 and
- Wenfeng An5,6
- 1 Washington State University;
- 2 Roswell Park Cancer Institute;
- 3 Max Delbrück Center for Molecular Medicine;
- 4 Paul Ehrlich Institute;
- 5 South Dakota State University
- ↵* Corresponding author; email: wenfeng.an{at}sdstate.edu
Abstract
Long interspersed elements (LINEs), through both self-mobilization and trans-mobilization of short interspersed elements and processed pseudogenes, have made an indelible impact on the structure and function of the human genome. One consequence is the creation of new CpG islands (CGIs). In fact, over half of all CGIs in the genome are associated with repetitive DNA, three quarters of which are derived from retrotransposons. However, little is known about the epigenetic impact of newly inserted CGIs. We utilized a transgenic LINE-1 mouse model and tracked DNA methylation dynamics of individual germline insertions during mouse development. The retrotransposed GFP marker sequence, a strong CGI, is hypomethylated in male germ cells but hypermethylated in somatic tissues, regardless of genomic location. The GFP marker is similarly methylated when delivered into the genome via the Sleeping Beauty DNA transposon, suggesting that the observed methylation pattern may be independent of the mode of insertion. Comparative analyses between empty and filled alleles further reveal a graded influence of the retrotransposed CGI on flanking CpG sites, a phenomenon that we described as 'sloping shores.' Computational analyses of human and mouse methylomic data at single base resolution confirm that sloping shores are universal for hypomethylated CGIs in sperm and somatic tissues. Additionally, the slope of a hypomethylated CGI can be affected by closely positioned CGI neighbors. Finally, by tracing sloping shore dynamics through embryonic and germ cell reprogramming, we found evidence of bookmarking, a mechanism that likely determines which CGIs will be eventually hyper- or hypomethylated.
- Received October 1, 2014.
- Accepted May 19, 2015.
- Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International license), as described at http://creativecommons.org/licenses/by/4.0/.
