Abstract
A battery of chromatin modifying enzymes play essential roles in remodeling the epigenome in the zygote and cleavage stage embryos, when the maternal genome is the sole contributor. Here we identify an exemption. DOT1L methylates lysine 79 in the globular domain of histone H3 (H3K79). Dot1l is an essential gene, as homozygous null mutant mouse embryos exhibit multiple developmental abnormalities and die before 11.5 days of gestation. To test if maternally deposited DOT1L is required for embryo development, we carried out a conditional Dot1l knockout in growing oocytes using the Zona pellucida 3-Cre (Zp3-Cre) transgenic mice. We found that the resulting maternal mutant Dot1lmat−/+ offspring displayed normal development and fertility, suggesting that the expression of the paternally inherited copy of Dot1l in the embryo is sufficient to support development. In addition, Dot1l maternal deletion did not affect the parental allele-specific expression of imprinted genes, indicating that DOT1L is not needed for imprint establishment in the oocyte or imprint protection in the zygote. In summary, uniquely and as opposed to other histone methyltransferases and histone marks, maternal DOT1L deposition and H3K79 methylation in the zygote and in the preimplantation stage embryo is dispensable for mouse development.
Highlights
A battery of chromatin modifying enzymes play essential roles in remodeling the epigenome in the zygote and cleavage stage embryos, when the maternal genome is the sole contributor
We found that H3K79me[3] is localized to DAPI-stained heterochromatin whereas H3K79me[2] is localized to DAPI-poor regions in mouse germ cells and somatic cells of the fetal gonad[29] In addition, we found that H3K79me[3] and H3K79me[2] generally cluster with repressive and active histone marks, respectively in chromosome-wide ChIP-chip mapping in mouse fibroblasts[30]
We found that H3K79me[3] and H3K79me[2] occupy reciprocal methylated versus unmethylated parental alleles of differentially methylated regions (DMRs) in the mouse[31]
Summary
A battery of chromatin modifying enzymes play essential roles in remodeling the epigenome in the zygote and cleavage stage embryos, when the maternal genome is the sole contributor. Because enzymes that catalyze the formation, or removal of covalent modifications of DNA and histone molecules carry out epigenome reprogramming in the early embryo, maternal effect of phenotype is observed for genes that encode chromatin-modifying enzymes[5,6,7,8,9,10,11,12,13,14,15]. Overexpression, as well as inactivation of Dot[1] suppressed silencing in position effect variegation (PEV) assays using reporter transgenes integrated at specific telomeric and pericentromeric loci[15,17,18,19] Later it was shown using H3K79 methylation-defective mutants and genome-wide expression analysis, that telomeric and pericentromeric silencing is not generally affected by Dot[1], as most telomeric and centromeric genes are not subject to H3K79 methylation-dependent natural s ilencing[19]. Based on earlier genetic s tudies[34,35,36,37,38] we expect that maternal mutation of Dot1l in the growing oocytes would eliminate the imprinted expression at those genes where the establishment of maternal imprints or the maintenance of maternal or paternal imprints depended on DOT1L
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