Chongyi Chen, Ph.D.

Our research seeks to establish DNA topology as a fundamental regulatory layer of genome function (COSB 2024). While DNA supercoiling has long been appreciated as a physical property of DNA, its spatial organization and regulatory roles in the human genome have remained largely unexplored.

To address this gap, we developed a quantitative genome-wide assay that profiles DNA supercoiling in living cells. Using this approach, we directly visualized both negative and positive twin-supercoiled domains surrounding active transcription units and, more importantly, uncovered large-scale supercoiling domains across the human genome that are dynamically modulated by topoisomerases (NSMB 2025). These domains colocalize with chromatin compartments but are largely independent of TAD structures, revealing a previously unrecognized dimension of genome organization.

Building on this discovery, we are investigating the mechanisms that generate and maintain topological homeostasis across the genome in human cells. We are particularly interested in how chromatin organization and dynamic chromatin processes, including transcription, SMC activity, and topoisomerase function, cooperate to shape genome-wide torsional landscapes. Our goal is to define the regulatory principles governing the formation, spatial distribution, and resolution of genomic supercoiling.

A central question in our lab is how DNA topology influences gene regulation. Our earlier work demonstrated that topoisomerase-controlled supercoiling dynamics drive transcriptional bursting in bacteria (Cell 2014). We are now extending these insights to human systems. To enable this, we have developed single-cell assays that simultaneously profile total and newly synthesized RNA (Genome Biology 2023; Cell Reports Methods 2026), allowing us to dissect how genomic supercoiling and topoisomerase activity modulate transcriptional dynamics, chromatin states, and gene expression programs at high resolution. In parallel, we investigate how disruption of topological homeostasis contributes to chromatin and gene misregulation in disease.

We also study how dysregulated supercoiling and aberrant topoisomerase activity promote genome instability and aberrations. Leveraging our expertise in detecting low-frequency genomic alterations (Science 2017), we examine how supercoiling tension and topoisomerase activities drive chromatin fragility, DNA damage, and genomic aberrations.

Through these integrated efforts, we seek to define the principles, mechanisms, and functional consequences of genome topology, and to reveal how this dynamic and fundamental layer of genome regulation interacts with chromatin organization, gene regulation, and genome stability in health and disease.

Dr. Chen earned his B.S. in biology from Peking University and his Ph.D. in biochemistry from Harvard University. During his doctoral studies in the lab of X. Sunney Xie, in collaboration with Xiaowei Zhuang’s lab, he investigated chromosome organization, DNA supercoiling dynamics, and gene expression noise in bacteria, utilizing advanced single-molecule imaging tools and the chromosome conformation capture assay. As a postdoctoral fellow at Harvard University, he was trained for genomic and single-cell technology development, and developed a new single-cell whole-genome amplification assay that enables accurate single-cell genome analyses in biology and medicine. He joined the Center for Cancer Research as an NIH Stadtman Investigator in October 2018.