November 14, 2025
A gentler chemistry from Chuan He’s lab improves accuracy and recovery of methylated DNA, advancing epigenetic research and diagnostics.
A new study from the laboratory of Professor Chuan He at the University of Chicago has developed an ultra-mild bisulfite (UMBS) sequencing technique that preserves DNA integrity, increases library yield, and improves methylation-call accuracy. The work builds upon the group’s earlier ultrafast bisulfite (UBS) chemistry and represents a major advancement in DNA methylation analysis.
A gentler approach to DNA methylation analysis
Bisulfite sequencing is a cornerstone technique for measuring DNA methylation, the epigenetic modification that regulates gene activity, but traditional methods use harsh chemical conditions that degrade DNA and limit sensitivity. This degradation has long hindered accurate methylation profiling from precious or limited samples such as early-stage embryos, single cells, or cell-free DNA from liquid biopsies. The He lab’s new ultra-mild bisulfite sequencing (UMBS) chemistry re-engineers this process from the ground up. By precisely controlling reaction conditions and introducing new stabilizing components, UMBS enables high conversion efficiency with minimal DNA damage that typically occurs during bisulfite treatment.
Improved yield and analytical precision
In their paper, the He group shows that UMBS demonstrated dramatically higher DNA recovery rates and more comprehensive CpG coverage than conventional bisulfite sequencing. The method also improved methylation-call accuracy across diverse sample types, from cultured cells to human tissue DNA. These advances pave the way for more quantitative and reproducible methylation measurements, critical for understanding epigenetic mechanisms in health and disease.
“Our goal was to make methylation sequencing both gentler and more precise for low- and ultra-low DNA inputs,” said Chuan He, HHMI Investigator and John T. Wilson Distinguished Service Professor in the Department of Chemistry, the Department of Biochemistry and Molecular Biology, and the Institute for Biophysical Dynamics. “UMBS provides a powerful tool for studying epigenetic changes in contexts that were previously inaccessible due to bisulfite’s DNA degradation.”
Building on previous breakthroughs
UMBS builds upon the He lab’s earlier fundamental ultrafast bisulfite (UBS) technique, which first showed that bisulfite reaction chemistry could be optimized for better DNA preservation. The new method refines this approach through further tuning of reaction parameters, enabling an even gentler and more efficient conversion.
“UMBS shows how fundamental insights on the bisulfite reaction mechanism can reshape an entire analytical field,” said Qing Dai, UChicago research professor and lead author on the study. “This chemistry allows us to recover far more DNA, opening opportunities for methylation analysis at unprecedented sensitivity.”
Broader implications and collaboration
The advance has implications across epigenetics, oncology, developmental biology, and clinical diagnostics, anywhere that limited DNA material restricts the ability to measure methylation accurately. The He lab’s bisulfite innovations have been exclusively licensed to Ellis Bio Inc., a biotechnology company working to adapt the UBS and UMBS chemistry for research kits.
“It’s been inspiring to see this chemistry evolve from a university lab discovery into a foundation for applied sequencing technologies,” said Ruitu Lyu, Incoming Chief Technology Officer at Ellis Bio.
Funding: The research was supported by the NIH and HHMI.