Researchers Identify Looping Silencers as a Promising Target for Cancer Treatment
Gene transcription is controlled largely by transcription factors that bind to enhancers, which are regions of the DNA that loop over to genes to activate them. While silencers have been hypothesized to work in a similar manner albeit to silence gene regulation, the understanding of gene repression mechanism remains elusive. In this study, researchers from the Cancer Science Institute of Singapore (CSI Singapore) have made inroads into identifying silencers, particularly looping silencers, and understanding their mechanisms of function.
Previous studies have identified looping silencers in mice and flies, however, none has been described in humans. Research team helmed by Dr. Melissa Fullwood has therefore embarked on this study to deepen their understanding on looping silencers in the human system.
H3K27me3 is an epigenetic modification to the DNA packaging protein Histone H3 which is associated with transcriptional repression. By using H3K27me3 ChIP-seq data, the group characterized H3K27me3-rich regions (MRRs) defined from clusters of H3K27me3 peaks in the genome. The team established that MRRs contain silencers in the human genome and developed a method for the identification of such silencer regions.
To delve deeper into understanding the repressive function of MRRs, the team utilized CRISPR excision and established that MRRs can control gene regulation by acting as silencers looping over to gene promoters. In addition, genes at or looping to MRRs were found to be more upregulated upon loss of H3K27me3 through EZH2 inhibition. EZH2 is known to be dysregulated or mutated in numerous cancers, such as lymphoma and leukemia. This suggests that looping silencers can have downstream impacts on gene regulation that promotes cancer growth, thereby making looping silencers a promising target for cancer treatment.
Moving forward, the researchers will examine the rationale and therapeutic merits of EZH2 inhibitors, while exploring additional drugs that can target looping silencers, as well as its effectiveness in stamping out cancer.