Sex-speciftic windows for high mRNA expression of DNA methyltransferases 1 and 3A and methyl-CpG-binding domain proteins 2 and 4 in human fetal gonads

DNA methyltransferases (DNMTs) and 5-methyl-CpG-binding domain proteins (MBDs) are involved in the acquisition of parent-specific epigenetic modifications in human male and female germ cells. Reverse Northern blot analyses demonstrated sex-specific differences in mRNA expression for the maintenance DNMT1 and the de novo DNMT3A in developing testis and ovary. In fetal testis DNMT1 and DNMT3A expression peaked in mitotically arrested spermatogonia around 21 weeks gestation. In fetal ovary transcriptional upregulation of DNMT1 and DNMT3A occurred during a very brief period at 16 weeks gestation, when the oocytes proceeded through meiotic prophase. Fetal gonads showed several fold higher DNMT3A expression levels than fetal brain and adult tissues. The most abundant DNMT3A isoform in fetal testis and ovary was DNMT3A2, whereas in all other analyzed tissues DNMT3A1 predominated. The catalytically inactive DNMT3A3 isoform was also present at relatively high levels in developing gonads and may perform a regulatory function(s). In both male and female fetal gonads expression of genes for MBD2 and MBD4, which may be implicated in chromatin remodeling of methylated genomic DNA sequences, was tightly linked to DNMT expression. We propose that the sex-specific time windows for concomitant upregulation of DNMT1, DNMT3A, MBD2, and MBD4 are associated with prenatal remethylation of the human male and female germ line.