I am an Assistant Staff member in the Departments of Microbial Sciences in Health and Cancer Sciences at Cleveland Clinic. My laboratory studies the fundamental principles of genome regulation in health and disease.
Approximately 98% of the human genome is noncoding, yet this vast regulatory landscape contains enhancers, promoters, insulators, and other elements that control when, where, and how genes are expressed. Together, these elements form a regulatory framework that is essential for development and cellular identity. Disruption of this regulatory genome—through genetic alterations or changes in genome organization—can contribute to a wide range of human diseases, including cancer and infectious diseases.
The Xie Lab seeks to understand the structure, dynamics, and molecular mechanisms of the human regulatory genome, with the long-term goal of translating fundamental discoveries into new opportunities for disease diagnosis, prevention, and treatment. We develop innovative molecular tools and integrate super-resolution live-cell imaging, high-throughput functional genomics, deep learning and computational modeling, and preclinical disease models. By bridging these complementary approaches, we aim to uncover how the genome is organized and regulated across space and time, and how these fundamental mechanisms are rewired in disease.
We are grateful for generous research support from the NIH (including the NIH Director’s New Innovator Award), the Mathers Foundation, the American Cancer Society, the Department of Defense, the Human Frontier Science Program, the Ohio Cancer Research Foundation, and the VeloSano community, among others.
We are interested in using high-resolution microscopy and high-throughput genomics to understand genome regulation in human development and diseases.
Research Information
Research Interests
My lab’s ongoing research includes:
(1) Genome 3D Architecture
The three-dimensional organization of the genome is fundamental to transcription, replication, and DNA repair. We previously developed 3D ATAC-PALM, a super-resolution imaging method that visualizes the spatial organization of regulatory DNA at nanometer resolution in single cells (Xie et al., Nature Methods, 2020). Building on this work, the Xie Lab develops new molecular, imaging, and computational tools to uncover how genome architecture regulates gene function in development and disease.
(2) Enhancer Grammar
Enhancers control gene expression across long genomic distances and are essential for developmental and tissue-specific transcriptional programs. Yet how enhancer sequences encode regulatory activity and communicate with their target genes remains incompletely understood. We combine deep learning, CRISPR genome engineering, and massively parallel functional assays to decode enhancer regulatory grammar and understand how it specifies precise gene expression across cell types and biological contexts.
(3) Regulatory Genome Dynamics
Gene regulation is inherently dynamic, yet most genomic approaches capture population-averaged snapshots. We develop technologies that combine genome engineering, live-cell super-resolution imaging, and quantitative computational analysis to visualize regulatory DNA, chromatin interactions, and transcriptional activity in individual living cells. These approaches allow us to investigate how genome organization and gene regulation unfold across space and time in their native cellular environment.
(4) Decoding the Cancer Genome
Cancer genomes can contain extrachromosomal DNA (ecDNA)—large, circular DNA molecules that amplify oncogenes and contribute to tumor heterogeneity, evolution, drug resistance, and poor clinical outcomes. Our previous work revealed that ecDNAs spatially cluster into nuclear hubs that enhance oncogene expression (King*, Yost*, Xie* et al., Nature, 2021). The Xie Lab now combines advanced imaging, functional genomics, and computational approaches to uncover how ecDNA is organized and regulated and to identify vulnerabilities that can be exploited for cancer therapy.