Maternal Setdb1 Is Required for Meiotic Progression and Preimplantation Development in Mouse

Abstract

Oocyte meiotic progression and maternal-to-zygote transition are accompanied by dynamic epigenetic changes. The functional significance of these changes and the key epigenetic regulators involved are largely unknown. Here we show that Setdb1, a lysine methyltransferase, controls the global level of histone H3 lysine 9 di-methyl (H3K9me2) mark in growing oocytes. Conditional deletion of Setdb1 in developing oocytes leads to meiotic arrest at the germinal vesicle and meiosis I stages, resulting in substantially fewer mature eggs. Embryos derived from these eggs exhibit severe defects in cell cycle progression, progressive delays in preimplantation development, and degeneration before reaching the blastocyst stage. Rescue experiments by expressing wild-type or inactive Setdb1 in Setdb1-deficient oocytes suggest that the catalytic activity of Setdb1 is essential for meiotic progression and early embryogenesis. Mechanistically, up-regulation of Cdc14b, a dual-specificity phosphatase that inhibits meiotic progression, greatly contributes to the meiotic arrest phenotype. Setdb1 deficiency also leads to derepression of transposons and increased DNA damage in oocytes, which likely also contribute to meiotic defects. Thus, Setdb1 is a maternal-effect gene that controls meiotic progression and is essential for early embryogenesis. Our results uncover an important link between the epigenetic machinery and the major signaling pathway governing meiotic progression.

Towards Functional Annotation of the Preimplantation Transcriptome: An RNAi Screen in Mammalian Embryos

“…In summary, GO term analysis offered no striking outliers in functional categories within our screen results and suggests that preimplantation development equally requires all aspects of cellular and molecular function for success. Supporting this notion, previous studies have found essential roles during preimplantation for genes within each of these functional categories (including DNA/RNA/protein binding4546, catalytic activity4748, various transporter activity495051). …”

The methyltransferase Setdb1 is essential for meiosis and mitosis in mouse oocytes and early embryos

“…While this manuscript was under review, Kim and colleagues (Kim et al, 2016) reported largely comparable findings on the role of maternal Setdb1 for meiosis and embryogenesis. In addition, they observed increased mRNA and protein expression for the Cdc14b phosphatase, a known negative regulator of meiotic maturation (Schindler and Schultz, 2009).…”

“…In addition, they observed increased mRNA and protein expression for the Cdc14b phosphatase, a known negative regulator of meiotic maturation (Schindler and Schultz, 2009). Using a siRNA-mediated knockdown approach, Kim et al (2016) characterized upregulated Cdc14b expression as the major driver of impaired meiotic progression in Setdb1 mutant oocytes. In our study, however, Cdc14b was not differentially expressed between Setdb1-deficient and control GV oocytes as determined by RNA sequencing analyses.…”

“…This finding is surprising as both laboratories studied the same conditional deletion allele of Setdb1 (Lohmann et al, 2010), yet on slightly different genetic backgrounds (C57Bl/6-129Sv hybrid versus C57Bl/6J). Moreover, in contrast to Kim et al (2016), we did not perform hormonal superovulation in any of the experiments dealing with oocyte maturation. Future experiments will be required to resolve this discrepancy.…”

Essential roles of Windei and nuclear monoubiquitination of Eggless/ SETDB 1 in transposon silencing

“…SETDB1 is the mammalian ortholog of Egg and is essential for viability . The loss of SETDB1 causes transposon silencing in embryonic stem cells and primordial germ cells in both sexes .…”