Regulation of MHCI genes in the CNS by DNA methylation

University Of California Los Angeles, Los Angeles CA

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Abstract

DESCRIPTION (provided by applicant): 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.