Role Of Maternal Sin3a In Reprogramming Gene Expression During Mouse Preimplantation Development

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Doctor of Philosophy (PhD)
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Cell & Molecular Biology
dormant maternal mRNA
maternal-to-zygotic transition
mouse preimplantation development
zygotic genome activation
Developmental Biology
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In mouse, the maternal-to-zygotic transition entails a dramatic reprogramming of gene expression during the course of zygotic genome activation, which is essential for continued development beyond the 2-cell stage. Superimposed on zygotic genome activation and reprogramming of gene expression is formation of a chromatin-mediated transcriptionally repressive state that promotes repression of genes at the 2-cell stage. Experimentally inducing global histone hyperacetylation relieves this repression and histone deacetylase 1 (HDAC1) is the major HDAC involved in the development of this transcriptionally repressive state. Because SIN3A is essential for mouse development and is part of a HDAC1/2-containing complex, I investigated the role of maternal SIN3A in the development of the global transcriptionally repressive state that develops during the course of genome activation and reprogramming. In addition, previous microarray data generated from our lab of oligo (dT) primed mouse oocyte and 1-cell embryo cDNA revealed an elevation in the relative abundance of the Sin3a transcript between the oocyte and 1-cell stages; the elevation in relative transcript abundance suggests that the Sin3a transcript undergoes translational recruitment during oocyte maturation because the elevation occurs during a period of transcriptional quiescence. Here I show that the Sin3a transcript is recruited for translation during oocyte maturation and following fertilization. I demonstrated that maternal SIN3A is essential for preimplantation development and the reprogramming of genes expression, because inhibiting the maturation-associated increase in SIN3A leads to an arrest in mouse embryonic development and unfaithful reprogramming of gene expression in 2-cell mouse embryos. The mid 1-cell embryo contains the maximum level of maternal SIN3A protein and the protein then rapidly decreases to essentially an undetectable level by the mid 2-cell stage; the rapid loss of maternal SIN3A is likely mediated by the proteasome because a proteasome inhibitor substantially inhibits the loss of maternal SIN3A. Due to the restricted presence of the maturation-associated increase in SIN3A, the function of maternal SIN3A is likely constrained to the 1-cell stage of mouse development. However, the increase in maternal SIN3A does not play a role in the minor ZGA, as depleting maternal SIN3A had no effect on global transcription in 1-cell embryos, but surprisingly results in histone hypoacetylation in 1-cell mouse embryos. Maintaining the presence of maternal SIN3A beyond the 1-cell stage had no effect on pre- and postimplantation development. Collectively, these findings indicate that the maturation-associated increase in SIN3A regulates the reprogramming of gene expression and the oocyte may utilize the translational recruitment of transcripts encoding chromatin-modifying-related factors during oocyte maturation as a post-transcriptional mechanism to faithfully execute the reprogramming of gene expression through the utilization of a maternally-derived transcription machinery.

Richard M. Schultz
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