"Epigenetic Plasticity and Intratumor Heterogeneity: Constraining Evolution to Prevent Invasion"
Paula Vertino, Ph.D.
Department of Radiation Oncology
Emory University School of Medicine
There is currently a great deal of interest in the epigenetic mechanisms that control transcription, and in particular in the targeting of post-initiation events as a new therapeutic strategy in human cancers. Our laboratory has been investigating the interdependent relationship between DNA methylation, local chromatin environment and histone modifying complexes in the regulation of RNA polymerase pausing dynamics and how local fine tuning of transcriptional output contributes to phenotypic plasticity and tumor progression. We find that one component of the transcriptional reprogramming that occurs during the epithelial to mesenchymal transition in breast epithelial cells is a shift in RNA polymerase pausing dynamics brought about by the locus-specific targeting of SUV420H2-mediated H4K20me3. We further find that RNA polymerase encounters not one but two major barriers to transcriptional elongation at CpG island associated genes, the well described 'promoter-proximal' pause and a second distal pause that occurs at the downstream edge of the CpG island domain that dominates at a subset. These findings lead us to propose that the relaxation of transcriptional constraints through the local modulation of RNA polymerase pausing dynamics, whether aberrant or intended, represents one component of the epigenetic plasticity that allows the emergence of tumor cell subpopulations with new invasive or drug resistant properties, and may be one mechanism by which epitherapeutics act to promote cancer cell reprogramming.