title: Retrotransposition creates sloping shores: a graded influence of hypomethylated CpG islands on flanking CpG sites.
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, more than 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 insertion- and non-insertion-containing 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.
authors.affiliation: School of Molecular Biosciences, Washington State University, Pullman, Washington 99164, USA;
authors.forename: Fiorella C
authors.initials: FC
authors.lastname: Grandi
authors.affiliation: School of Molecular Biosciences, Washington State University, Pullman, Washington 99164, USA;
authors.forename: James M
authors.initials: JM
authors.lastname: Rosser
authors.affiliation: School of Molecular Biosciences, Washington State University, Pullman, Washington 99164, USA; Department of Pharmaceutical Sciences, South Dakota State University, Brookings, South Dakota 57007, USA;
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Newkirk
authors.affiliation: School of Molecular Biosciences, Washington State University, Pullman, Washington 99164, USA;
authors.forename: Jun
authors.initials: J
authors.lastname: Yin
authors.affiliation: The Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics and Genetics Program, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Jiang
authors.affiliation: The Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics and Genetics Program, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Xing
authors.affiliation: School of Molecular Biosciences, Washington State University, Pullman, Washington 99164, USA;
authors.forename: Leanne
authors.initials: L
authors.lastname: Whitmore
authors.affiliation: Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany;
authors.forename: Sanum
authors.initials: S
authors.lastname: Bashir
authors.affiliation: Division of Medical Biotechnology, Paul Ehrlich Institute, 63225 Langen, Germany.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Ivics
authors.affiliation: Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany;
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Izsvák
authors.affiliation: School of Molecular Biosciences, Washington State University, Pullman, Washington 99164, USA;
authors.forename: Ping
authors.initials: P
authors.lastname: Ye
authors.affiliation: The Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics and Genetics Program, Roswell Park Cancer Institute, Buffalo, New York 14263, USA;
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Yu
authors.affiliation: Department of Pharmaceutical Sciences, South Dakota State University, Brookings, South Dakota 57007, USA;
authors.forename: Wenfeng
authors.initials: W
authors.lastname: An
mesh_terms: D000818:Animals; D019295:Computational Biology / Q000379:methods; D018899:CpG Islands; D019175:DNA Methylation; D004251:DNA Transposable Elements; D044127:Epigenesis, Genetic; D016678:Genome; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics* / Q000254:growth & development*; D013094:Spermatozoa / Q000254:growth & development
chemical_list: D004251:DNA Transposable Elements