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Abnormal regulation of DNA methyltransferase expression in cloned mouse embryos
Young Gie Chung1, Sarayu Ratnam, J Richard Chaillet
1The Fels Institute for Cancer Research and Molecular Biology and Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Abstract:
Cloning by somatic cell nuclear transfer is inefficient. This is evident in the significant attrition in the number of surviving cloned offspring at virtually all stages of embryonic and fetal development. We find that cloned preimplantation mouse embryos aberrantly express the somatic form of the Dnmt1 DNA (cytosine-5) methyltransferase, the expression of which is normally prevented by a posttranscriptional mechanism. Additionally, the maternal oocyte-derived Dnmt1o isoform undergoes little or none of its expected translocation to embryonic nuclei at the eight-cell stage. Such defects in the regulation of Dnmt1s and Dnmt1o expression and cytoplasmic-nuclear trafficking may prevent clones from completing essential early developmental events. Furthermore, aberrant Dnmt1 localization and expression may contribute to the defects in DNA methylation and the developmental abnormalities seen in cloned mammals.
Insights
Somatic cell nuclear transfer cloning is inefficient due to developmental attrition. Cloned embryos show aberrant DNA methyltransferase (Dnmt1) expression and nuclear trafficking, hindering early development and causing abnormalities.
Area of Science:
- Developmental Biology
- Epigenetics
- Mammalian Reproduction
Background:
- Somatic cell nuclear transfer (SCNT) cloning exhibits low efficiency, marked by high rates of embryonic and fetal developmental failure.
- The precise molecular mechanisms underlying SCNT inefficiencies remain incompletely understood.
Purpose of the Study:
- To investigate the expression and localization of DNA methyltransferase 1 (Dnmt1) in cloned preimplantation mouse embryos.
- To identify potential epigenetic defects contributing to developmental abnormalities in cloned mammals.
Main Methods:
- Analysis of Dnmt1 expression patterns in cloned mouse embryos.
- Assessment of Dnmt1 isoform (Dnmt1s and Dnmt1o) localization and trafficking during early embryonic development.
Main Results:
- Cloned preimplantation embryos aberrantly express the somatic Dnmt1 isoform (Dnmt1s).
- The oocyte-derived Dnmt1 isoform (Dnmt1o) fails to translocate properly to embryonic nuclei at the eight-cell stage.
- Defects in Dnmt1 regulation and nuclear import are observed in cloned embryos.
Conclusions:
- Aberrant Dnmt1 expression and disrupted cytoplasmic-nuclear trafficking of Dnmt1 isoforms are implicated in SCNT inefficiencies.
- These epigenetic dysregulations may impede crucial early developmental events and contribute to developmental abnormalities in cloned offspring.