Critical period of nonpromoter DNA methylation acquisition during prenatal male germ cell development

• Published in: PloS one 2011-09, Vol.6 (9), p.e24156-e24156
• Main Authors: Niles, Kirsten M, Chan, Donovan, La Salle, Sophie, Oakes, Christopher C, Trasler, Jacquetta M
• Format: Article
• Language: English
• Subjects: Analysis; Anemia; Animal tissues; Animals; Biology; Cells (biology); Children & youth; Chromosomes, Mammalian - genetics; Critical period; Deoxyribonucleic acid; Diet; DNA; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - deficiency; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA Methylation; DNA methyltransferase; DNA Methyltransferase 3A; DNA Methyltransferase 3B; DNA, Intergenic - genetics; Embryo, Mammalian - embryology; Embryo, Mammalian - metabolism; Embryos; Epigenetic inheritance; Epigenetics; Female; Fertility; Gene expression; Gene Expression Regulation, Developmental; Gene Expression Regulation, Enzymologic; Gene sequencing; Genetics; Genomes; Germ cells; Linear Models; Loci; Male; Medical research; Mice; Mice, Knockout; Mice, Transgenic; Nucleotide sequence; Pediatrics; Pharmacology; Reverse Transcriptase Polymerase Chain Reaction; Sperm; Spermatogenesis; Spermatogenesis - genetics; Spermatozoa - growth & development; Spermatozoa - metabolism; Stem cells; Time Factors; Trends; Windows (intervals)
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0024156

The prenatal period of germ cell development is a key time of epigenetic programming in the male, a window of development that has been shown to be influenced by maternal factors such as dietary methyl donor supply. DNA methylation occurring outside of promoter regions differs significantly between sperm and somatic tissues and has recently been linked with the regulation of gene expression during development as well as successful germline development. We examined DNA methylation at nonpromoter, intergenic sequences in purified prenatal and postnatal germ cells isolated from wildtype mice and mice deficient in the DNA methyltransferase cofactor DNMT3L. Erasure of the parental DNA methylation pattern occurred by 13.5 days post coitum (dpc) with the exception of approximately 8% of loci demonstrating incomplete erasure. For most loci, DNA methylation acquisition occurred between embryonic day 13.5 to 16.5 indicating that the key phase of epigenetic pattern establishment for intergenic sequences in male germ cells occurs prior to birth. In DNMT3L-deficient germ cells at 16.5 dpc, average DNA methylation levels were low, about 30% of wildtype levels; however, by postnatal day 6, about half of the DNMT3L deficiency-specific hypomethylated loci had acquired normal methylation levels. Those loci normally methylated earliest in the prenatal period were the least affected in the DNMT3L-deficient mice, suggesting that some loci may be more susceptible than others to perturbations occurring prenatally. These results indicate that the critical period of DNA methylation programming of nonpromoter, intergenic sequences occurs in male germline progenitor cells in the prenatal period, a time when external perturbations of epigenetic patterns could result in diminished fertility.