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Abstract
After fertilization, the sperm and oocyte genomes undergo extensive epigenetic reprogramming to form a totipotent zygote. The dynamic epigenetic changes during early embryo development primarily involve DNA methylation and demethylation. We have previously identified Gse (gonad-specific expression gene) to be expressed specifically in germ cells and early embryos. Its encoded protein GSE is predominantly localized in the nuclei of cells from the zygote to blastocyst stages, suggesting possible roles in the epigenetic changes occurring during early embryo development. Here, we report the involvement of GSE in epigenetic reprogramming of the paternal genome during mouse zygote development. Preferential binding of GSE to the paternal chromatin was observed from pronuclear stage 2 (PN2) onward. A knockdown of GSE by antisense RNA in oocytes produced no apparent effect on the first and second cell cycles in preimplantation embryos, but caused a significant reduction in the loss of 5-methylcytosine (5mC) and the accumulation of 5-hydroxymethylcytosine (5hmC) in the paternal pronucleus. Furthermore, DNA methylation levels in CpG sites of LINE1 transposable elements, Lemd1, Nanog and the upstream regulatory region of the Oct4 (also known as Pou5f1) gene were clearly increased in GSE-knockdown zygotes at mid-pronuclear stages (PN3-4), but the imprinted H19-differential methylated region was not affected. Importantly, DNA immunoprecipitation of 5mC and 5hmC also indicates that knockdown of GSE in zygotes resulted in a significant reduction of the conversion of 5mC to 5hmC on LINE1. Therefore, our results suggest an important role of maternal GSE for mediating active DNA demethylation in the zygote.
Highlights
Resetting and modification of epigenetic marks as a part of epigenetic reprogramming occur in the genomes of early embryos and primordial germ cells (PGCs) [1,2,3,4,5]
We demonstrated here that GSE was present in both pronuclei, the protein was associated tightly and predominantly with the paternal chromatin architecture from pronuclear stage 2 (PN2) onward, at which point active DNA demethylation commenced
The chromatin-bound PGC7/Dppa3/Stella is a small protein (,17 kDa) and is predominantly confined to the maternal pronucleus during zygote development, resulting in a change in chromatin configuration [12,13]. These above findings lead us to propose that GSE and PGC7/Dppa3/Stella might act in a competitive fashion to block one another’s association with chromatin
Summary
Resetting and modification of epigenetic marks as a part of epigenetic reprogramming occur in the genomes of early embryos and primordial germ cells (PGCs) [1,2,3,4,5]. Unraveling the mechanism of epigenetic reprogramming will provide important information on the characterization of germ cells, comprising totipotent and unipotent cells possessing an underlying genomic plasticity [6,7]. Both sperm and oocyte genomes undergo epigenetic reprogramming under the control of maternal factors immediately after fertilization. The rapid reduction of 5-methylcytosine (5 mC) content in the paternal genome before first DNA replication is the reset of epigenetic memory, classified as active DNA demethylation [1,3,8] This DNA demethylation of the paternal genome is linked to global conversion of 5 mC to 5-hydroxymethylcytosine (5 hmC) catalyzed by the maternally encoded enzyme Tet methylcytosine dioxygenase 3 (Tet3), which is intensely expressed in oocytes and zygotes [9,10,11]. The mechanisms underlying DNA demethylation in early embryogenesis are not well understood [14]
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