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云南快乐10分开奖结果:EHMT2 and SETDB1 protect the maternal pronucleus from 5mC oxidation
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The most important task of the mammalian zygote is to globally remodel its epigenome. Chromosomes that carried out sperm or oocyte functions are remodeled toward directing the unique totipotent state that characterizes the healthy preimplantation-stage embryo. The guiding differences in cell functions are marked on the chromosomes by interdependent epigenetic modifications including histone and DNA methylation, which both undergo global changes in the zygote. By performing genetic experiments, we found that two maternally supplied histone methyltransferase enzymes play important roles in the zygote in specifying the process of global DNA remodeling by 5-methylcytosine oxidation.
Genome-wide DNA “demethylation” in the zygote involves global TET3-mediated oxidation of 5‐methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) in the paternal pronucleus. Asymmetrically enriched histone H3K9 methylation in the maternal pronucleus was suggested to protect the underlying DNA from 5mC conversion. We hypothesized that an H3K9 methyltransferase enzyme, either EHMT2 or SETDB1, must be expressed in the oocyte to specify the asymmetry of 5mC oxidation. To test these possibilities, we genetically deleted the catalytic domain of either EHMT2 or SETDB1 in growing oocytes and achieved significant reduction of global H3K9me2 or H3K9me3 levels, respectively, in the maternal pronucleus. We found that the asymmetry of global 5mC oxidation was significantly reduced in the zygotes that carried maternal mutation of either the Ehmt2 or Setdb1 genes. Whereas the levels of 5hmC, 5fC, and 5caC increased, 5mC levels decreased in the mutant maternal pronuclei. H3K9me3-rich rings around the nucleolar-like bodies retained 5mC in the maternal mutant zygotes, suggesting that the pericentromeric heterochromatin regions are protected from DNA demethylation independently of EHMT2 and SETDB1. We observed that the maternal pronuclei expanded in size in the mutant zygotes and contained a significantly increased number of nucleolar-like bodies compared with normal zygotes. These findings suggest that oocyte-derived EHMT2 and SETDB1 enzymes have roles in regulating 5mC oxidation and in the structural aspects of zygote development.
?1Present address: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824.
- ?2To whom correspondence may be addressed. Email: .
Author contributions: P.E.S. designed research; T.-B.Z. and L.H. performed research; T.-B.Z., N.P., G.P.P., and P.E.S. analyzed data; and T.-B.Z., G.P.P., and P.E.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1819946116/-/DCSupplemental.
Published under the PNAS license.