Delineating interplay between epigenetic pathways

Abstract

Aberrant DNA methylation is commonly observed in cancer genomes, including focal gene promoter hypermethylation and global hypomethylation. While the gain of this repressive epigenetic modification at gene promoter has been relatively well studied, global loss of DNA methylation in cancer cells remains poorly understood. As previously reported, the loss of DNA methylation results in the formation of partially methylated domains (PMDs), large genomic segments with reduced DNA methylation. Intriguingly, genes residing in PMDs show little to no transcriptional change, potentially compensated by the histone H3 lysine 9 tri-methylation (H3K9me3) and histone H3 lysine 27 tri-methylation (H3K27me3) repressive histone modifications. We have observed that large PMDs are typically enriched with both of these repressive epigenetic marks in a particular pattern. Therefore, we hypothesize that occupancy of H3K27me3 at the boundaries might act as a barrier in demarcating PMDs. Using A375, a melanoma cell line, as a model, we employed techniques to analyze the epigenome including whole genome bisulfite sequencing (MethylC-seq) and chromatin immunoprecipitation sequencing (ChIP-seq). Furthermore, we utilized several approaches to engineer either the genomic sequence or epigenomic marks at PMDs boundaries and studied their effects on other epigenetic marks. This study aims to elucidate the interplay between distinct epigenetic modifications.

Date of Award	2018
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology