DNA methylation-mediated nucleosome dynamics and oncogenic Ras signaling: insights from FAS, FAS ligand and RASSF1A.

Cytosine methylation at the 5-carbon position is the only known stable base modification found in the mammalian genome. The organization and modification of chromatin is a key factor in programming gene expression patterns. Recent findings suggest that DNA methylation at the junction of transcription initiation and elongation plays a critical role in suppression of transcription. This effect is mechanistically mediated by the state of chromatin modification. DNA methylation attracts binding of methyl-CpG-binding domain proteins that trigger repression of transcription, whereas DNA demethylation facilitates transcription activation. Understanding the rules that guide differential gene expression, as well as transcription dynamics and transcript abundance, has proven to be a taxing problem for molecular biologists and oncologists alike. The use of novel molecular modeling methods is providing exciting insights into the challenging problem of how methylation mediates chromatin dynamics. New data implicate lipid rafts as the coordinators of signals emanating from the cell membrane and are converging on the mechanisms linking DNA methylation and chromatin dynamics. This review focuses on some of these recent advances and uses lipid-raft-facilitated Ras signaling as a paradigm for understanding DNA methylation, chromatin dynamics and apoptosis.