Methylation of cytosines in CpG dinucleotides is an important step in epigenetic regulation of the genome. The status of CpG methylation can influence the expression of genes, as methylated cytosines can repress the start of transcription whereas unmethylated cytosines maintain an open chromatin structure. Previous studies have shown the importance of retaining normal methylation patterns in the prevention of cancer. Dnmtl is a maintenance methyltranferase that preferentially methylates hemi-methylated DNA after replication. Conditional deletion of this gene in the CNS results in hypomethylated cells. As part of an array study on Dnmtl -/- mice, we discovered that the MHC I loci genes are significantly up regulated. Furthermore, expression of MHC I genes is necessary for proper CNS development. Thus, the goal of this project is to understand the mechanism by which methylation affects the expression of MHCI genes. We will explore three possible mechanisms of regulation- 1. Direct methylation of the MHCI promoter blocks transcription factor binding. 2. Methylation regulates the expression of upstream transcriptional regulators. 3. Methylation directly or indirectly influences the chromatin remodeling of the MHC I promoter.
| Fouse, Shaun D; Shen, Yin; Pellegrini, Matteo et al. (2008) Promoter CpG methylation contributes to ES cell gene regulation in parallel with Oct4/Nanog, PcG complex, and histone H3 K4/K27 trimethylation. Cell Stem Cell 2:160-9 |
| Shen, Yin; Matsuno, Youko; Fouse, Shaun D et al. (2008) X-inactivation in female human embryonic stem cells is in a nonrandom pattern and prone to epigenetic alterations. Proc Natl Acad Sci U S A 105:4709-14 |
| Feng, Jian; Fouse, Shaun; Fan, Guoping (2007) Epigenetic regulation of neural gene expression and neuronal function. Pediatr Res 61:58R-63R |
