This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Genomic imprinting involves modification of a gene or chromosomal region that results in the differential expression of maternal and paternal alleles. Disruption or inappropriate expression of imprinted genes results in several clinically significant syndromes and tumorigenesis in humans. The goal of this project is to study the allele-specific expression pattern of 4 imprinted genes in monkey preimplantation embryos and embryonic stem cells (ESCs). As a prerequisite for this research objective, we identified single nucleotide polymorphisms (SNPs) in the monkey genome that are relevant to determining the parent-specific expression and methylation status of NDN, H19, SNRPN and IGF2. Based on the existence of SNPs, we have shown an aberrant biallelic expression of IGF2 and H19 in several monkey ESC lines while SNRPN and NDN were normally imprinted and expressed from the maternal allele. In contrast, expanded blastocyst-stage embryos, from which these ESCs were derived, exhibited normal paternal expression of IGF2 and maternal expression of H19 suggesting that imprinting marks for these genes were established at this stage of development. Thus, it is clear that the relaxed imprinting of IGF2 and H19 in monkey ESCs occurred during establishment or the initial culture of ESCs. We also showed that this pattern of expression was retained in differentiated neuronal lineages derived from these ESCs indicating, perhaps, irreversible loss of imprinting at this locus. Thus, rhesus macaque embryos and ESCs offer an accurate imprinting model to study the impact of assisted reproductive technologies (ARTs) as well as the safety and efficacy of ESC-based medical treatments.
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