Liangqi (Frank) Xie, PhD
Assistant Staff
Email: [email protected]
Location: Cleveland Clinic Main Campus
Research
Ninety-eight percent of the human genome is noncoding and harbors regulatory elements—such as enhancers, promoters, and insulators—that serve as the blueprint for human development. This regulatory genome is a hotspot for genetic alterations that contribute to a wide range of diseases, including infections and cancer. The Xie Lab is dedicated to deciphering the structure, dynamics, and mechanisms of the human regulatory genome to improve the diagnosis, prevention, and treatment of human diseases. To achieve this, we develop novel molecular tools and integrate super-resolution imaging, high-throughput functional genomics, advanced deep learning/ computational approaches, and diverse preclinical models. Our multidisciplinary strategy aims to uncover fundamental principles of genome regulation in both health and disease contexts.
Biography
Dr. Xie is an Assistant Staff member in the Departments of Infection Biology and Cancer Biology at the Cleveland Clinic and an Associate Member of the NCI-designated Case Comprehensive Cancer Center.
Education & Professional Highlights
Dr. Xie received his medical degree from Peking University in China and earned his Ph.D. from Oregon Health & Science University in the United States. Dr. Xie completed his postdoctoral training under the mentorship of Dr. Robert Tjian from the Howard Hughes Medical Institute at the University of California, Berkeley. Prior to joining the Cleveland Clinic, he conducted collaborative research with Dr. James Zhe Liu at the Janelia Research Campus of the Howard Hughes Medical Institute. The Xie lab research has been supported by awards from National Institutes of Health (NIH Director's New Innovator Award), United States Department of Defense, American Cancer Society, Human Frontier Science Program, Ohio Cancer Research, Mathers Foundation, and VeloSano community.
Research
(1) Genome 3D Architecture The genome serves as the blueprint for storing, propagating, and expressing genetic information. Understanding its three-dimensional architecture is fundamental to dissecting essential DNA-templated processes such as transcription, replication, and repair. To this end, we previously developed a super-resolution imaging technique, 3D ATAC-PALM, which enables in situ, single-cell visualization of the spatial organization of regulatory DNA elements (e.g., enhancers, promoters, insulators) at nanometer resolution (Xie et al., Nature Methods, 2020). Building on this foundation, the Xie Lab continues to innovate new molecular and computational tools to decode the structural organization of the mammalian genome and investigate how this architecture influences genome function in both development and diseases such as cancer.
(2) Enhancer Grammar Among the diverse types of cis-regulatory DNA elements within the accessible genome, enhancers are unique in their ability to regulate gene expression across long genomic distances—ranging from kilobases to megabases—relative to their target promoters. These elements orchestrate developmental stage- and tissue-specific transcriptional programs, and their dysregulation is implicated in numerous developmental disorders and diseases. However, how distal enhancers are spatially and temporally organized to communicate with their target promoters remains a central, unresolved question in the field of transcriptional regulation. To address this, we are developing deep learning–based models to decode the underlying grammar of enhancers that drive precise spatiotemporal gene expression. These predictions are being systematically validated using CRISPR genome editing combined with massively parallel functional assays.
(3) Regulatory Genome Dynamics Most current approaches for studying genome regulation rely on population-averaged, time-averaged snapshot assays. While these methods have been foundational in establishing our current understanding of gene regulation, they are limited in their ability to capture the dynamic, spatially compartmentalized, and functionally heterogeneous nature of chromosomes within individual living cells. A critical knowledge gap remains: we currently lack the tools to (1) label regulatory elements at scale within the complex and heterogeneous nuclear landscape, (2) visualize high-dimensional and dynamic chromatin interactions with sufficient spatial and temporal resolution, and (3) quantitatively infer molecular activity at single-molecule resolution in live cells. To overcome these limitations, we are developing an integrated platform that combines innovative genome engineering strategies, live-cell super-resolution imaging, and a quantitative analytical framework. This technology will enable direct interrogation of the regulatory genome within its native, dynamic cellular context, offering unprecedented insights into the real-time mechanisms that govern genome function.
(4) Decoding the Cancer Genome Beyond conventional structural variations such as insertions, deletions, and translocations, oncogenes and their regulatory elements can exist in the form of extrachromosomal DNA (ecDNA)—large (~megabase-sized), highly amplified (~hundreds of copies), circular DNA structures. These ecDNAs are emerging as key drivers of oncogene overexpression, intratumoral heterogeneity, cancer evolution, drug resistance, and poor clinical outcomes. Recognizing their pivotal role in cancer biology, ecDNA has been designated a Cancer Grand Challenge. In collaboration with Drs. Howard Chang and Paul Mischel at Stanford, our prior work (King*, Yost*, Xie* et al., Nature, 2021) revealed that ecDNAs spatially cluster into nuclear hubs that amplify oncogene expression. At the Cleveland Clinic, the Xie Lab is building on this discovery by developing cutting-edge microscopy, genomic, and computational approaches to study the dynamics, regulation, and therapeutic vulnerabilities of ecDNA in cancer.
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.
Our Team
Selected Publications
Selected publications:
1. Dong P, Zhang S, Gandin V, Xie L, …, Chang H, Liu Z (2024). Organization of the 3D genome encodes gene co-expression programs in single cells. Nature Genetics. 2024 Aug;56(8):1654-1664. doi: 10.1038/s41588-024-01852-1
2. Lange J, Rose J, Chen C, Pichugin Y, Xie L, …, Mischel P (2022). The evolutionary dynamics of extrachromosomal DNA in human cancers. Nature Genetics. 2022 Sep 19. doi: 10.1038/s41588-022-01177-x
3. Xie L, Dong P, Qi Y,…, Zhang B*, Tjian R*, Liu Z* (2022). BRD2 Compartmentalizes the Accessible Genome. Nature Genetics. Apr;54(4):481-491.
4. Hung KL*, Yost KL*, Xie L*, …, Mischel P, Liu Z, Chang H (2021). EcDNA hubs drive cooperative intermolecular oncogene expression. Nature. *,co-first author
5. Xie L, Liu Z (2021). Single cell Imaging of Genome Organization and Dynamics. Mol Syst. Biol. Jul;17(7):e9653
6. Grimm J, Xie L, …, Lavis L (2021). Deuteration improves small-molecule fluorophores. JACS Au. May 24;1(5):690-696
7. Grimm JB, Tkachuk AN, Xie L, …, Lavis L. (2020) A general method to optimize and functionalize red-shifted rhodamine dyes. Nature Methods. 17(8):815-821
8. Xie L, Dong P, …, Tjian* R, Liu Z* (2020). 3D ATAC-PALM: super-resolution imaging of the accessible genome. Nature Methods. 17(4):430-436
9. An L, Bhargava-Shah A, Xie L, Darzacq X, Tjian R (2018). A stable mode of bookmarking by TBP recruits RNA Polymerase II to mitotic chromosomes. eLife.7.pii: e35621
10. Xie L, Torigoe SE, …, Tjian R (2017). A Dynamic Interplay of Enhancer Elements Regulates Klf4 expression in Naïve-pluripotency. Genes & Development. 31(17):1795-1808
11. Knight SC, Xie L, …, Doudna JA*, Tjian R* (2015). Dynamics of CRISPR-Cas9 genome interrogation in living cells. Science. 350(6262):823-6
Careers
Single Cell Multiomics and Cancer Genome Regulation
A postdoctoral position is available in Frank Xie lab at the Cleveland Clinic Lerner Research Institute (LRI) and Case Comprehensive Cancer Center. The postdoctoral fellow is expected to study two funded directions: (1) Single-cell multi-omics of the spatiotemporal regulation of brain tumor development (NIH); and (2) Epigenomic mechanisms in cancer and immunity (NIH/DOD).
The Xie lab is located in the historic city of Cleveland, Ohio, where the 100-year-old Cleveland Clinic is ranked as one of the top two national hospital systems. Xie Lab develops unique tools and integrates super-resolution imaging, high-throughput sequencing, and genome engineering approaches to study fundamental regulatory mechanisms in development and disease (e.g., cancer). Representative research articles include: Xie et al., Nature Methods, 2020; Xie et al, Nature Genetics, 2022; King*, Yost*, Xie* et al., Nature, 2021; Xie et al., Mol.Sys.Bio, 2021; Xie et al., Genes & Development, 2017; Knight, Xie et al., Science, 2015. More details can be found at https://frankxielab.com/.
The Xie lab currently has 5 postdoctoral fellows, 1 Ph.D. Student, and 2 research technicians. We are building a multidisciplinary team of biologists, physicians, data scientists, tool builders, engineers, and others to study the frontiers of genome regulation in development, cancer, and immunity. We hope to apply our basic findings to translational medicine. We are recruiting one more enthusiastic and motivated postdoctoral researcher to study emerging questions about single cell biology and cancer genome regulation. Candidates should have a Ph.D. and/or M.D. degree with a proven track record of research publications (e.g., peer-reviewed first author articles) and excellent English communication skills. In this recruitment cycle, preference will be given to self-driven and detail-oriented candidates with prior solid experience in molecular biology and computational biology.
Postdoctoral salaries are based on NIH standards and commensurate with past research experience. Excellent Cleveland Clinic’s insurance and benefit packages are included. Successful candidates will have access to Cleveland Clinic’s vast computational (e.g., IBM Quantum Computing), clinical, and medical resources and collaborate with physician scientists and clinicians to translate benchside research to bedside. Postdoctoral fellows will conduct mentored independent research, lead cutting-edge projects, gain solid research experience, and participate in guided collaborations, with the encouragement to develop unconventional ideas, risky projects, and cross-disciplinary frontiers. By the end of the training, postdoctoral candidates are anticipated to be equipped with top-tier journal publications, critical thinking, multidisciplinary mindsets, and excellent communication skills competitive for their next level of career advancement.
Interested individuals should directly email Dr. Liangqi (Frank) Xie at [email protected] and [email protected] with the title line as Xie_lab_Postdoc_Application The postdoctoral fellow application material must include the following information.
1) A cover letter describing prior research background, future research interests, career goals, and estimated start time.
2) A CV, including publications and contact information for 3 referees.
Research News
The 2023 NIH Director’s Award funds projects with potential to change the trajectory of biomedical science.