Bulletin No. 2, 2019

09 They Stand on the Shoulders of Giants Revealer of DNA Secrets Every cell in our body contains the same DNA, but why can one cell become cancerous while another does not? It partly originates from the myriad interactions between genes and the enhancer ‘switches’ that turn them on or off. Prof. Kevin Yip rises to the challenge to identify the target genes of the enhancers in gene regulation and explain the consequences of aberrations in the enhancers. The human genome is represented by a string of around three billion letters. Leveraging machine learning to analyse an archive of about 1,000 samples of human cells and tissue samples and cell lines, Professor Yip created the largest enhancer-target gene resource. The large- scale public data sets were taken from the ENCODE, FANTOM5 and Roadmap Epigenomics consortia, public platforms offering data for biomedical research. Professor Yip looked into the samples through computer models to establish connections between the genes and enhancers in the DNA from both healthy and diseased tissues of different people. This requires a vast number of calculations to establish whether the various genes within one chromosome and their many enhancers are actually interacting with each other. ‘That’s just the first level: there could be a false signal, the enhancer could be there just by chance, or it may be controlling the gene indirectly,’ Professor Yip explains. ‘We try to build predictive models, so that we can make predictions for individual samples in a sample-specific manner.’ Prof. Alfred Cheng , a liver-cancer expert in the School of Biomedical Sciences, guided Professor Yip in his work by identifying the aberrations of enhancers specific to liver cancer and those generally present in all types of cancers. With a focus on liver- cancer cells, Professor Yip succeeded in identifying three genes– PSRC1, RBM24 and TERT –that become hyperactive in that cancer due to a ‘perturbation’ or disturbance by different enhancers. It’s possible to remove those enhancers, reversing the activation of the problematic genes. The team was able to edit the genome using CRISPR/Cas9, which allows scientists to edit a DNA sequence. Scientists may then move on to create treatments such as drugs that disrupt the activity of the enhancer. ‘I appreciate the freedom given me at CUHK to work on any research topic. Colleagues in different Faculties are highly collaborative, too,’ says Professor Yip. His findings have been published in the journal Nature Genetics . ‘I appreciate the freedom given me at CUHK to work on any research topic. Colleagues in different Faculties are highly collaborative, too.’