Nuclear-cytoplasmic interactions in mammalian embryos

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Reproductive success is the single most important measurement of progress of animal breeding programs. However, reproductive success in high-performing domestic animals is significantly compromised by elevated embryonic mortality during gestation and postnatal morbidity. This is particularly true in gestations resulting from assisted reproductive techniques (ART) such as the in vitro production of embryos and somatic cell nuclear transfer (SCNT). In these animals, little is known of the etiology of the developmental abnormalities associated with ART, which include the Large Offspring Syndrome, indicating that further research is needed to elucidate the biological mechanisms and to improve the efficiency of ART for animal breeding practices. Therefore, my research interests are aimed at exploring the epigenetic phenomena of cell reprogramming with emphasis on those involved in the pre- and postnatal developmental losses caused by ART. Chromatin remodeling is a key feature of the successful reprogramming by SCNT and in derivation of induced pluripotent stem (iPS) cells. Genomic imprinting is an epigenetic phenomenon that enables the monoallelic expression of a group of developmentally important genes in a parent-of-origin fashion through the allele-specific methylation of differentially methylated regions. Since most imprinted genes have been studied in laboratory animals, preliminary characterization of these imprinted control regions is required to enable studies in the large animals. Therefore, my principal objective is to improve our understanding of the epigenetic interactions between nuclei and cytoplasm during chromatin remodelling in mammals, particularly in domestic species. Our hypothesis is that the reprogramming of somatic cell nuclei involves epigenetic modification directed by cytoplasmic components that allow normal spatial and temporal patterns of gene expression during early development. The specific objectives are to (1) characterize the epigenetic anomalies associated with success and failure during development of embryos derived by ART, particularly in vitro fertilization and consequent in vitro culture, SCNT and pluripotent stem cells, and (2) investigate the molecular mechanisms controlling the erasure and establishment of epigenetic marks in the differentially methylated regions of imprinted genes and their parental-specific and overall expression patterns. Together, the findings from this research program will have significant impact on our understanding of the epigenetic mechanisms of chromatin reprogramming during early development in large domestic animals, providing a better understanding of how the oocyte is able to effectively reprogram somatic nuclei. In practice, these studies will enable the creation of novel and improved tools that assure a safe and efficient use of ART in farm animal breeding practices.**