Consequences of the depletion of zygotic and embryonic enhancer of zeste 2 during preimplantation mouse development

Abstract

Enhancer of zeste 2 (Ezh2), a SET domain-containing protein, is crucial for development in many model organisms, including early mouse development. In mice, Ezh2 is detected as a maternally inherited protein in the oocyte but its function at the onset of development is unknown. We have used a conditional allele of Ezh2 to deplete the oocyte of this maternal inheritance. We show that the loss of maternal Ezh2 has a long-term effect causing severe growth retardation of neonates despite 'rescue' through embryonic transcription from the paternal allele. This phenotypic effect on growth could be attributed to the asymmetric localisation of the Ezh2/Eed complex and the associated histone methylation pattern to the maternal genome, which is disrupted in Ezh2 mutant zygotes. During subsequent development, we detect distinct histone methylation patterns in the trophectoderm and the pluripotent epiblast. In the latter where Oct4 expression continues from the zygote onwards, the Ezh2/Eed complex apparently establishes a unique epigenetic state and plasticity, which probably explains why loss of Ezh2 is early embryonic lethal and obligatory for the derivation of pluripotent embryonic stem cells. By contrast, in the differentiating trophectoderm cells where Oct4 expression is progressively downregulated Ezh2/Eed complex is recruited transiently to one X chromosome in female embryos at the onset of X-inactivation. This accumulation and the associated histone methylation are also lost in Ezh2 mutants, suggesting a role in X inactivation. Thus, Ezh2 has significant and diverse roles during early development, as well as during the establishment of the first differentiated cells, the trophectoderm, and of the pluripotent epiblast cells.Supplemental data available online

Supplementation of fetal bovine serum alters histone modification H3R26me2 during preimplantation development of in vitro produced bovine embryos

“…In human embryos, H3K27me3 is relatively static to the 8-cell stage, where it declines, increasing again at the blastocyst stage (Zhang et al 2012). In mice blastocysts, H3K27me3 is asymmetrically distributed between the ICM and trophoblast cells, as well as being enriched on the inactive X chromosome in the trophectoderm (Erhardt et al 2003, Dahl et al 2010. Human embryos also have dynamic changes in the permissive histone mark, H3K4me3 during development to the blastocyst stage (Zhang et al 2012).…”

“…The highly dynamic marks are often associated with critical events, such as the transition to embryonic genome activation or the first cellular differentiation from totipotent cells into the inner cell mass and trophectoderm [for review see Mason et al 2012). Two examples are trimethylation of lysines 9 and 27 of histone H3 which are enriched in the ICM compared with the trophectoderm (Erhardt et al 2003). Epigenetic modifications are related to important stages of embryonic development.…”

Characterization of non-canonical Polycomb Repressive Complex 1 subunits during early mouse embryogenesis

“…4,14 Among them, H3K27me3, catalyzed by the Polycomb Repressive Complex 2 (PRC2) and, in general, Polycomb group (PcG) proteins have been shown to play important roles from the earliest stages of development. 8,25,27 At large, PcG repression is achieved through 2 major types of complexes that mediate various biochemical functions including histone modifying activities, recognition of covalent modifications, and physical compaction of chromatin. PRC2 displays its main catalytic activity toward H3K27me3 while the main catalytic activity of PRC1 is monoubiquitylation of H2A at lysine 119 (K119), although PRC1 has also been shown to be able to compact chromatin independently of H2AK119ub in vitro and in vivo.…”

Early epigenetic reprogramming in fertilized, cloned, and parthenogenetic embryos

“…These changes include the large scale 42 positioning of chromosomes and genes within the nucleus as well as local modifications to 43 DNA and chromatin [6] and [7]. Epigenetic changes affect the accessibility of DNA to the 44 transcription machinery, hence, gene expression [6] and [7]. Local modifications include Moreover, all these local modifications may specifically recruit factors, as in recruitment of 48 bromodomain proteins to acetylated histones and of chromobox family proteins to methylated 49 histones [9].…”

“…1). The "early mammalian" or "preimplantation" embryo development whereas in the TE it is only present in the inactivated X chromosome [44].…”