Peter Lewis, PHD
Studies how molecules that “coat” the DNA in our cells can regulate cellular function and influence how cancer cells grow and respond to treatment.
H3F3A (encoding the histone variant H3.3) mutations are likely driver mutations for non-brainstem pediatric high-grade astrocytoma (HGA; G34R/V in 22%-31%). The mechanism of the G34R/V mutations remains poorly understood. In unpublished studies, Dr. Lewis’s laboratory has found that the G34R substitution causes high levels of H3K27me3, a modification linked to gene repression, on the mutant H3.3 protein. His team found that expression of H3.3-G34R exhibit selective loss of H3K27ac, a modification linked to enhancer activity, on a subset of gene enhancers. The coupled loss of H3K27ac and gain of H3K27me3 on H3.3-G34R nucleosomes led to loss of enhancer activity and decreased gene expression. These and other data lead Dr. Lewis to hypothesize that PRC2-mediated gene repression is required for H3.3-G34Rcontaining HGAs. Dr. Lewis’s research proposes to 1) investigate how genome-wide alterations in histone modifications by H3.3-G34R mutations are reflected at the genome level of polycomb complex distribution and gene expression; and 2) to assess the dependence of polycomb function in H3.3-G34R-containing HGAs using genetic and pharmacologic strategies. To assess the dependence of polycomb function in G34Rcontaining HGAs, he will use pharmacological and genetic strategies to interfere with the activities of polycomb complexes. Commercially available EZHl/2 inhibitors and siRNAs directed against polycomb subunits will be used for in vitro cell growth assays and in vivo xenograft studies. Additionally, transcriptome and Ch IP sequencing will be employed to monitor changes in gene expression and chromatin modifications upon siRNA or drug treatment. Dr. Lewis expects that loss of polycomb silencing may partially or fully suppress the effects of the G34R mutation.