After training as a chemist, I became interested in epigenetics during my Ph.D. in Dr. Chuan He’s lab at the University of Chicago. I then did postdoctoral study in Dr. Stephen Quake’s lab at Stanford University, where I further developed my interest in using epigenetic information for clinical applications. I joined the Ludwig Institute for Cancer Research, Oxford Branch in June 2016 as an Assistant Member, where my group has been developing technologies in epigenetics and applying them to elucidate epigenetic mechanisms in tumour biology and develop clinical applications in epigenetics.
I am interested in epigenetics not only because the versatile chemical groups found in epigenetic modifications offer a wonderland for a chemist to play with in an otherwise bland genome, but also because these epigenetic modifications are very important in biology. The two major epigenetic modifications in human DNA are 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), both derived from cytosine, which play crucial roles in a broad range of biological processes from gene regulation to normal development. More importantly, changes in the abundance and location of 5mC and 5hmC are associated with various diseases, and abnormal patterns of 5mC and 5hmC are hallmarks of cancer. Therefore, as one could imagine, being able to map 5mC and 5hmC is invaluable for both basic research and clinical applications. In particular, one of my key aims is to sequence 5mC and 5hmC in circulating cell-free DNA from the blood for non-invasive early cancer detection.
However, before we can do that, we need the right tools. The current gold standard for 5mC and 5hmC sequencing, bisulphite sequencing, has always been an unsatisfactory method due to its indirect detection and harsh chemical treatment, which damages most of the DNA in the samples. Recently, we developed TAPS (TET-assisted pyridine borane sequencing), a mild bisulphite-free and base-resolution sequencing method that detects 5mC and 5hmC directly without affecting unmodified cytosines. TAPS could replace bisulphite sequencing as the new standard in DNA epigenetic analysis and could have wide applications in academic research and clinical diagnostics.
Currently, we are applying TAPS to the following research areas:
- Epigenetic sequencing of the circulating cell-free DNA to develop a non-invasive early cancer detection assay;
- Single-cell epigenetic sequencing to study the heterogeneity of tumours;
- Combining with third-generation sequencing technologies such as SMRT sequencing and nanopore sequencing for long-read epigenetic sequencing.
Bisulfite-free direct detection of 5-methylcytosine and 5-hydroxymethylcytosine at base resolution.
Liu Y. et al, (2019), Nature biotechnology, 37, 424 - 429
Bisulfite-free and base-resolution analysis of 5-methylcytidine and 5-hydroxymethylcytidine in RNA with peroxotungstate
Yuan F. et al, (2019), Chemical Communications, 55, 2328 - 2331
Subtraction-free and bisulfite-free specific sequencing of 5-methylcytosine and its oxidized derivatives at base resolution
Liu Y. et al, (2021), Nature Communications, 12
Cell-free DNA TAPS provides multimodal information for early cancer detection.
Siejka-Zielińska P. et al, (2021), Science advances, 7
Endonuclease enrichment TAPS for cost-effective genome-wide base-resolution DNA methylation detection.
Cheng J. et al, (2021), Nucleic acids research, 49