Histone arginine methylation and malignant progression
PRMT1 and PRMT5 contribute to the epigenetic regulation of gene expression through arginine methylation of histone tails (most notably H4R3me2a, H4R3me2s and H3R2me2s). Unlike histone lysine methylation, a comprehensive global analysis of the contribution of histone arginine methylation to gene expression, and its comparison between healthy and cancer cells is largely lacking. Building on our analysis of the FOXP1 promoter in BCSCs, we are now taking a genomics (RNA-Seq and ChIP-Seq) approach to obtain a global profile of how PRMT5 differentially epigenetically regulates gene expression in BCSCs compared to the differentiated bulk tumour cell population.
To understand the epigenetic role of PRMT1 in breast cancer, we are establishing chemical-biology approaches that enable chemical labelling of PRMT1-deposited histone marks that are then amenable to click-chemistry and affinity purification. This bio-orthogonal approach (first developed by Minkui Luo, MSKCC) substitutes the need of SAM, the methyl cofactor, with that of a synthetic analogue. This has major advantages as it enables ChIP-Seq analysis without the need of antibody-mediated DNA isolation. By comparing the bio-orthogonal profile between healthy and breast cancer cells we will be able to deduce mechanisms by which PRMT1 transcriptionally regulates this disease.