title: Contribution of intragenic DNA methylation in mouse gametic DNA methylomes to establish oocyte-specific heritable marks.
abstract: Genome-wide dynamic changes in DNA methylation are indispensable for germline development and genomic imprinting in mammals. Here, we report single-base resolution DNA methylome and transcriptome maps of mouse germ cells, generated using whole-genome shotgun bisulfite sequencing and cDNA sequencing (mRNA-seq). Oocyte genomes showed a significant positive correlation between mRNA transcript levels and methylation of the transcribed region. Sperm genomes had nearly complete coverage of methylation, except in the CpG-rich regions, and showed a significant negative correlation between gene expression and promoter methylation. Thus, these methylome maps revealed that oocytes and sperms are widely different in the extent and distribution of DNA methylation. Furthermore, a comparison of oocyte and sperm methylomes identified more than 1,600 CpG islands differentially methylated in oocytes and sperm (germline differentially methylated regions, gDMRs), in addition to the known imprinting control regions (ICRs). About half of these differentially methylated DNA sequences appear to be at least partially resistant to the global DNA demethylation that occurs during preimplantation development. In the absence of Dnmt3L, neither methylation of most oocyte-methylated gDMRs nor intragenic methylation was observed. There was also genome-wide hypomethylation, and partial methylation at particular retrotransposons, while maintaining global gene expression, in oocytes. Along with the identification of the many Dnmt3L-dependent gDMRs at intragenic regions, the present results suggest that oocyte methylation can be divided into 2 types: Dnmt3L-dependent methylation, which is required for maternal methylation imprinting, and Dnmt3L-independent methylation, which might be essential for endogenous retroviral DNA silencing. The present data provide entirely new perspectives on the evaluation of epigenetic markers in germline cells.
authors.affiliation: Department of BioScience, Tokyo University of Agriculture, Tokyo, Japan.
authors.forename: Hisato
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sakurai
authors.forename: Misaki
authors.initials: M
authors.lastname: Imai
authors.forename: Nozomi
authors.initials: N
authors.lastname: Takahashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fukuda
authors.forename: Obata
authors.initials: O
authors.lastname: Yayoi
authors.forename: Shun
authors.initials: S
authors.lastname: Sato
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakabayashi
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Hata
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sotomaru
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kono
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000378:metabolism; D018899:CpG Islands / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D018076:DNA, Complementary; D044127:Epigenesis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D016678:Genome; D055106:Genome-Wide Association Study; D018392:Genomic Imprinting; D005854:Germ Cells / Q000254:growth & development / Q000378:metabolism*; D059014:High-Throughput Nucleotide Sequencing; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009865:Oocytes / Q000378:metabolism*; D013094:Spermatozoa / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D018076:DNA, Complementary; C498796:Dnmt3l protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases