Epigenetic regulation, driven by the dynamic interplay between the genome and the environment, is a cornerstone of development and disease. The Ren Lab investigates how gene activity is modulated through DNA methylation, histone modifications, and non-coding RNAs, with a primary focus on higher-order chromatin architecture. We were among the first to establish phase separation as a fundamental mechanism governing the spatial organization of epigenetic information. To dissect these processes, we pioneered live-cell single-molecule tracking to quantify epigenetic dynamics in real time. Our multidisciplinary approach integrates high-resolution imaging with cutting-edge genomics (CUT&RUN, Micro-C, Hi-C), proteomics, and CRISPR/Cas9 engineering to address the most pressing questions in chromatin biology.
Ongoing Research Topics:
1. Exploring the Roles of Phase Separation in Gene Regulation: Our lab has been at the forefront of defining how Polycomb group (PcG) proteins organize chromatin through phase separation (JBC, 2018). We have demonstrated that these phase-separated environments accelerate the target search process (Cell Reports, 2020) and assemble in a precise, composition- and concentration-dependent manner (Cell Reports, 2023). Most recently, we revealed that phase separation is a critical regulator of the deposition and spreading of the H3K27me3 mark (Molecular Cell, 2026). Together, these findings provide a foundation for our current research: investigating how phase separation dictates gene expression programs and contributes to development and disease.
2. Single-Molecule Imaging of Epigenetic Processes: Epigenetic regulation is a highly dynamic process that requires factors to efficiently locate and bind specific chromatin targets. Observing these interactions in real-time is essential to understanding how regulatory functions are executed. Using live-cell single-molecule tracking, we discovered that CBX-PRC1 complexes are targeted to chromatin via dual recognition of H3K27me3 and DNA (eLife, 2016). Our research further revealed that the H3K27M mutation in DIPG brain tumors disrupts the PRC2 target-search process, a finding that challenged the prevailing ‘trap’ mechanism (Nature Communications, 2018). We also demonstrated that phase separation significantly enhances target-search efficiency (Cell Reports, 2020, and Molecular Cell, 2026). By continually advancing these single-molecule techniques, we visualize and quantify epigenetic mechanisms with unprecedented resolution.
3. Epigenetic Mechanisms in Cancers: Diffuse Intrinsic Pontine Gliomas (DIPGs) are primarily driven by the H3.3K27M oncohistone mutation, yet the precise impact on PcG protein function has remained elusive. Our research has provided critical mechanistic insights into this pathology: we demonstrated that H3.3K27M prolongs both the residence and search times of EZH2, while selectively increasing the search time and decreasing the bound fraction of CBX7 (Nature Communications, 2018). Building on our discovery that phase separation governs the spatial organization of PcG proteins (Cell Reports, 2023) and is essential for H3K27me3 deposition (Molecular Cell, 2026), we are currently investigating how the disruption of phase separation contributes to the epigenetic dysregulation observed in DIPG.
