While the vast majority of autosomal genes are expressed from both parental alleles, a small subset of genes, most of which are involved with development, growth and behavior, are expressed from only one allele. These genes are said to be imprinted, as it was initially hypothesized that an epigenetic mark was present on one of the alleles to prevent its transcription. Mutations in imprinted genes are responsible for a number of diseases, including Prader-Willi Syndrome and pseudohypoparathyroidism. The goal of this grant is to discover and explain the underlying mechanisms governing the imprinting of genes. Two specific areas are targeted for intense investigation: 1. Deciphering the Histone Code: It has recently been shown that histones may be modified by acetylation, methylation, phosphorylation, and ubiquitination, and that these modifications may regulate gene transcription. These studies will determine if there is a specific or characteristic histone code that signals to the cell's transcriptional machinery that a gene is imprinted and that only one of the alleles should be transcribed. 2. The Epigenome in Cancer and Development: DNA methylation has been shown to be an important component of the imprinting process, as differentially methylated regions are often associated with gene silencing. Using a novel methylated oligonucleotide approach, it will be possible to add methyl groups to a specific region of a gene and thereby induce specific DNA methylation changes to learn how region-specific methylation can alter the imprinting process. The role of methylation patterns in imprinted genes that have lost imprinting in malignant tissues will also be examined. These aspects of the control of genomic imprinting are closely inter-related and inter-dependent phenomena, and advances in one area will provide new insights into the other mechanisms governing transcriptional control. Ultimately, it will be possible to develop a comprehensive chromatin/DNA model of imprinting. ? ?
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