Mentor: Professor Tamara Davis
The forms and functions of organisms are dependent on the regulation of gene expression. This is attained by regulating gene activity at specific developmental stages or in specific tissues. In order for proper growth and development to take place, it is important that developmentally important genes can either stay in inactive or active states which are inherited in the soma. For other developmentally important genes, the level of expression must be regulated. Genomic imprinting is one mechanism in which expression levels are controlled. Although most genes are expressed from both copies, imprinted genes are only expressed from one of the two paternal alleles. In order to achieve this parent of origin-specific expression, the two alleles (copies) must be marked.
Studies have shown that the epigenetic control of gene expression in mammals is achieved by DNA methylation. Here, epigenetic can be defined as the changes in gene expression without change in nucleotide sequence. DNA methylation is the addition of methyl groups at cytosine residues in CpG dinucleotides in the DNA. Many imprinted genes studied in the past have differentially methylated regions (DMRs) where one allele is methylated and the other is unmethylated. This modification can serve to mark parental origin of each allele and many also play a role in regulating gene expression.
Our research focuses on one of the imprinted genes in mice, Rasgrf1. Rasgrf1 is a guanine nucleotide exchange factor gene. It is known as playing a role in long-term memory formation and growth control. In Rasgrf1, the expression pattern varies in different tissues. It is expressed solely from paternal allele in the brain; other tissues may have no expression, or have expression from both parental alleles. It is also found that Rasgrf1 is methylated on the paternal, expressed allele. A differentially methylated region is proposed to control imprinted expression. But, we have shown that differential methylation is present in all tissues, regardless of expression state. Therefore, there isn’t a direct correlation between methylation and expression of particular allele.
Our lab is interested in studying the tissue-specific regulation of gene expression of Ras gene and the relationship between DNA methylation and imprinted expression. We want to determine its role in expression. We are currently examining the methylation status of a potentially methylated region near the Ras promoter site in order to identify any other DMRs around Ras gene. If differential methylation correlates with different expression, this region may play a role in regulating expression of Rasgrf1. If this region lacks differential methylation, then there is no corresponding relationship between differential methylation and imprinted expression.