Grant: Discovery Grants Program - Individual

IDENTIFICATION AND EVOLUTIONARY COMPARISON OF IMPRINTING CENTERS      Genomic imprinting is a specialized transcriptional regulatory mechanism that restricts expression to the maternally- or paternally-inherited copy of a gene. An intriguing characteristic of imprinted genes is that they often cluster in larger chromosomal domains that are regulated by imprinting centers. Comparative analysis of four imprinted domains in mouse and humans revealed that while there is some commonality, various silencing mechanisms are employed by different imprinting domains. Thus, despite the many advances that have been made since the identification of the first imprinted gene, the nature of the imprinting center and its mode of action have remained elusive. The short term objectives of this research proposal are (1) to identify putative imprinting centers and (2) to perform comparative analysis of imprinting clusters while the long-term objectives are to perform molecular characterization of imprinting centers and their associated imprinted domains across mammalian and non-mammalian species.      Preimplantation is a unique period in mammalian development . It is the ONLY time when the entire genome undergoes global demethylation with the likely exception of imprinting centers where methylation is maintained. Taking advantageous of this unique developmental feature, I will develop a novel procedure for the isolation of DNA sequences that retain methylation in late morula - early blastocysts. Once these elements are identified, their imprinted status will be confirmed. Comparative analysis of current genomic databases will be performed on imprinting centers and surrounding regions among different mammals and other vertebrates.      This study will be the first of its kind to utilize the unique developmental feature of preimplantation development to identify imprinting centers. Data generated from this study will allow comparative analysis of a larger number of imprinting centers and will lead to a greater understanding of the molecular mechanisms regulating imprinting and the evolution of genomic imprinting.