Jumonji domain-containing protein 3 regulates histone 3 lysine 27 methylation during bovine preimplantation development

Abstract

Understanding the mechanisms of epigenetic remodeling that follow fertilization is a fundamental step toward understanding the bases of early embryonic development and pluripotency. Extensive and dynamic chromatin remodeling is observed after fertilization, including DNA methylation and histone modifications. These changes underlie the transition from gametic to embryonic chromatin and are thought to facilitate embryonic genome activation. In particular, trimethylation of histone 3 lysine 27 (H3K27me3) is associated with gene-specific transcription repression. Global levels of this epigenetic mark are high in oocyte chromatin and decrease to minimal levels at the time of embryonic genome activation. We provide evidence that the decrease in H3K27me3 observed during early development is cell-cycle independent, suggesting an active mechanism for removal of this epigenetic mark. Among H3K27me3-specific demethylases, Jumonji domain-containing protein 3 (JMJD3), but not ubiquitously transcribed tetratricopeptide repeat X (UTX), present high transcript levels in oocytes. Soon after fertilization JMJD3 protein levels increase, concurrent with a decrease in mRNA levels. This pattern of expression suggests maternal inheritance of JMJD3. Knockdown of JMJD3 by siRNA injection in parthenogenetically activated metaphase II oocytes resulted in inhibition of the H3K27me3 decrease normally observed in preimplantation embryos. Moreover, knockdown of JMJD3 in oocytes reduced the rate of blastocyst development. Overall, these results indicate that JMJD3 is involved in active demethylation of H3K27me3 during early embryo development and that this mark plays an important role during the progression of embryos to blastocysts.G amete nuclei undergo extensive chromatin remodeling soon after fertilization, including alterations to DNA methylation levels and posttranslational histone tail modification. These changes are known to influence chromatin structure and transcriptional readout (1) and also to promote embryonic genome activation (EGA) (2), which occurs in humans and cows after three to four cell divisions (3-5). Because the first few cell divisions occur without embryonic gene transcription, maternally inherited mRNA and proteins present in the oocyte are likely responsible for inducing these epigenetic changes (6).Histone lysine methylation is involved in transcriptional repression and/or activation and plays a key role during lineage specification and cell differentiation (7). Di-and trimethylation of histone 3 lysine 27 (H3K27) are catalyzed by the polycomb repressive complex 2 (PRC2), which has three essential components: enhancer of zeste homolog 2 (EZH2), embryonic ectoderm development (EED), and suppressor of zeste 12 (SUZ12) (8-10). These epigenetic marks are specifically associated with gene repression (11) and are typical of many key developmental genes in embryonic stem cells, stem cell maintenance (12-14), and regulation of pluripotency (15). In mouse embryos, asymmetric distribution of trimethylated H3K27 (H3K27me3) i...

Jmjd3 Controls Mesodermal and Cardiovascular Differentiation of Embryonic Stem Cells

“…The Jmjd3 −/− mice that we have generated out of the ESCs, used in the present study, showed embryonic lethality before E6.5, suggesting a crucial role of Jmjd3 in early embryonic development Figure VII). This is consistent with the requirement of Jmjd3 for blastocyst development, 27 but is in contrast to other studies which showed that Jmjd3-deficient mice are perinatal lethal. 12,28 The discrepancy between the phenotypes of Jmjd3…”

EED and KDM6B Coordinate the First Mammalian Cell Lineage Commitment To Ensure Embryo Implantation

“…Methylation at the H3K27 residue is mediated by the PRC2 complex (31), and demethylation is mediated by histone demethylases KDM6A (also known as UTX) and KDM6B (also known as JMJD3) (32). A recent study showed that KDM6B is involved in regulating global H3K27Me3 levels in bovine preimplantation embryos (33). In addition, studies in mESCs showed that JARID2 (also known as Jumonji) orchestrates PRC2 function and fine-tunes deposition of the H3K27Me3 mark at chromatin domains (34)(35)(36)).…”

Histone H3 lysine 27 trimethylation acts as an epigenetic barrier in porcine nuclear reprogramming

“…H3K27me3 has a great effect on embryonic development. For example, the embryonic development was reduced after inhibition of H3K27me3 removal in bovine (Canovas et al 2012). Similarly, iPS reprogramming process was also accompanied by genome wide H3K27me3 changes, and the aberrant dynamics of H3K27me3 would impair iPS cells induction (Mikkelsen et al 2008, Hawkins et al 2010, Mansour et al 2012.…”