The human genome is a DNA library that contains an entire set of genetic instructions for the body to work. Besides the genetic code to create our proteins, it is also made up of genomic elements such as enhancers and silencers that help regulate gene expression. Cancer is a disease characterized by the growth of abnormal cells in an uncontrolled manner, resulting from changes in gene expression. Many cancers are deadly, making it critical to discover new treatments for cancer.
These DNA sequences function like a switch to “turn on” (enhancers) and “turn off” (silencers) the promoter region – a region necessary to start the coding – of a gene making them an attractive target to control gene expression. Enhancers do this by looping over to the promoter as if they were touching the switch. However, it is unknown whether silencers do this in the human genome.
This is because scientifically, it is generally more difficult to identify silencers compared to enhancers in the human body leading to a much poorer understanding of silencers in the world of molecular biology.
However, a team of scientists led by Assistant Professor Melissa Fullwood from the NTU School of Biological Sciences and Cancer Science Institute of Singapore in collaboration with Professor Greg Tucker-Kellogg at the Department of Biological Sciences, National University of Singapore has taken up the challenge and in a recent study successfully identified a method to study on how silencers can be identified by looking for H3K27me3-rich regions, and discovered the first silencers that loop to regulate its target genes in the human genome.
From left to right: Asst Prof Fullwood, Dr Cai Yichao and Ms Zhang Ying
Silencers & H3K27me3
Opposite to the functions of an enhancer, silencers prevent gene expression. In Asst Prof Fullwood’s research, the team developed a method to identify silencers in the human genome – the use of H3K27me3-rich regions. The study suggests that the manipulation of these H3K27me3-rich regions could be a potential way for regulating silencers and thus, be useful in treating cancer.
H3K27me3 describes the epigenetic modification to Histone H3, the protein responsible for DNA packaging. To be precise, it is the addition of three methyl groups on a specific lysine amino acid, in the Histone H3 protein.
Asst Prof Fullwood and her team scanned through analytical data and identified clusters of H3K27me3. Two examples of clusters of H3K27me3 were then experimentally confirmed as silencers and were shown to be able to loop over to genes to control their gene expression. They showed that silencer removal causes looping changes, cell identity changes and led to cell growth inhibition. Since cell growth is critical for cancer cells to survive, targeting silencers could be a way to treat cancer in the future.
SBS Assistant Professor Melissa Jane Fullwood
Post-doctoral fellow Dr Cai Yichao
PhD student Ms Zhang Ying
Discovery
The H3K27me3-rich regions function as silencers in the human body, in which this study showed the first-ever silencers that loop to its target genes to regulate them, in the same manner, that enhancers regulate genes. The study has the potential to target cancer in the future by inhibiting proteins that control silencers.
Read more about how the research was conducted here.