Cambridge, MA - Traditional bisulfite sequencing damages DNA, while enzyme-based alternatives are inconsistent. A novel methylation analysis method, called UMBS-seq, was published this week in Nature Communications. UMBS-seq achieves both accuracy and gentleness, unlocking more reliable cancer biomarker detection. The method, which was initially developed by researchers at The University of Chicago, will be made commercially available to cancer diagnostic test developers by Ellis Bio early next year.
Why methylation analysis matters for cancer
Every cell in the human body carries the same DNA sequence, yet cells behave differently because of epigenetic marks, which are chemical modifications that regulate which genes turn on or off. One of the most important and abundant epigenetic marks is DNA methylation, in which a small chemical tag called 5-methylcytosine (5mC) attaches to DNA to control gene expression.
Abnormal DNA methylation patterns are a hallmark of cancer and can turn tumor suppressor genes off or turn cancer-promoting oncogenes on in tumor cells. They also hold tremendous promise for early cancer detection, monitoring treatment response, and matching patients to precision therapies. To fully realize that promise, scientists need methods that can accurately read these methylation patterns from even the tiniest, most fragile DNA fragments, such as those circulating in a patient's blood.
The problem with existing methylation analysis technologies
For decades, the gold standard for studying methylation has been bisulfite sequencing, a chemistry that converts unmethylated cytosines into another base so that sequencing can distinguish methylated from unmethylated sites. But the harsh bisulfite reaction often shreds DNA, leading to bias, poor recovery, and inaccurate methylation estimates. These limitations have hindered bisulfite sequencing methods on short, delicate DNA pieces found in liquid biopsies or formalin-fixed tumor samples.
To avoid that damage, newer enzyme-based approaches such as enzymatic methyl-seq (EM-seq) have been developed. These gentler reactions rely on enzymes instead of chemicals to read methylation marks. However, they tend to have time-intensive and complex workflows and also produce higher false positives that can especially confound results using very low DNA inputs.
The solution: Ultra-Mild Bisulfite Sequencing (UMBS-seq)
The University of Chicago research team, led by Professor Chuan He, developed a new method called Ultra-Mild Bisulfite Sequencing (UMBS-seq), which re-engineers the bisulfite chemistry itself. By fine-tuning the bisulfite formulation and reaction conditions, they successfully achieved nearly-complete cytosine conversion under ultra-mild conditions while preserving DNA integrity.
In head-to-head evaluations, UMBS-seq consistently outperformed both conventional bisulfite and enzymatic sequencing methods across all major performance metrics:
- Higher library yield and integrity
- Improved library complexity and better genomic coverage
- Exceptional conversion efficiency and highly accurate DNA methylation calls
- Streamlined workflow that is simpler and faster than enzyme-based conversion methods
When applied to human subject cell-free DNA samples, the type used for non-invasive cancer diagnostics in liquid biopsies, UMBS-seq preserved DNA integrity and generated more complete coverage of cancer-related methylation sites than leading commercial kits. The researchers envision UMBS-seq becoming the new standard for DNA methylation sequencing in both research and diagnostic settings, enabling more sensitive, reproducible, accurate, and cost-effective analysis of epigenetic changes in cancer and beyond. The newly developed method has been exclusively licensed to Ellis Bio Inc, a biotechnology company working to adapt this technology for research tools that can ultimately be validated for clinical testing. Ellis Bio currently has an early-access program open for its UMBS-based SuperMethylTM Max kit.
"With UMBS-seq and the SuperMethyl Max kit that Ellis Bio developed based on UMBS, we can now read cancer's epigenetic code without destroying the very few and precious molecules we need to study," said Ruitu Lyu, Incoming Chief Technology Officer at Ellis Bio, who co-authored the UMBS-seq study. "It's a practical, scalable solution that could accelerate the clinical use of methylation biomarkers for early detection and personalized therapy."
About Ellis Bio
Ellis Bio, Inc. is developing multi-omic tools and technologies that enable researchers, clinicians, and drug developers to capture the full complexity of the DNA and RNA landscape with a portfolio of products that goes beyond sequencing to provide insights on the DNA and RNA modifications that drive gene expression – collectively known as the epigenome and epitranscriptome.
