Sox2 enhancer clusters in a living mouse embryonic stem cell.
3D super-resolution genome imaging
We develop super-resolution methods to visualize the nano-scale organization of the 3D genome. Using lattice light-sheet microscopy and residence-time thresholding at the single-molecule level, we can systematically map stable transcription factor (TF) binding sites in single live cells (Liu et al, 2014; Xie & Dong et al, 2022). Another method, 3D ATAC-PALM, combines ATAC (Assay for Transposase-Accessible Chromatin) with lattice light-sheet PALM microscopy to selectively image nano-scale structures of the accessible genome (Xie & Peng et al, 2020). These methods, combined with chemical and genetic perturbations, allow us to investigate the molecular identities and interactions that contribute to the formation and maintenance of 3D genome organization. We found that disease-inducing protein hubs promote clustering of accessible chromatin (Cai et al, 2019; Liu et al, 2023). The genome architectural protein CTCF decompacts accessible chromatin (Xie & Dong et al, 2020). In contrast, cohesin prevents spatial mixing of accessible chromatin by counterbalancing affinity interactions mediated by Brd2 (Xie & Dong et al, 2022).
Related Publications
1. Liu, Z.@, Legant, WR., Chen, B., Li, L., Grimm, JB., Lavis, LD., Betzig, E. and Tjian, R. (2014). 3D imaging of Sox2 enhancer clusters in embryonic stem cells. eLife, 3:e04236.
2. Xie, L.*, Dong, P.*, Qi, Y., Marzio, M.D., Chen, X., Banala, S., Legant, W.R., English, B., Hansen, A., Schulmann, A., Lavis, L.D., Betzig, E., Chang, H.Y., Zhang, B., Tjian, R.@, Liu, Z.@ (2020). 3D ATAC-PALM: super-resolution imaging of the accessible genome. Nature Methods, 17(4):430-436.
3. Xie, L.*, Dong, P.*, Qi, Y., Hsieh, T.S., English, B., Jung, S., Chen, X., Marzio, M.D., Chen, X., Casellas, R., Chang, H.Y., Zhang, B.@, Tjian, R.@, Liu, Z.@ (2022) BRD2 Compartmentalizes the Accessible Genome. Nature Genetics, 54(4):481-491.
Collaborations:
1. Cai, D., Feliciano, D., Dong, P., Flores, E., Gruebele, M., Porat-Shliom, N., Sukenik, S., Liu, Z., Lippincott-Schwartz., J. (2019). Phase separation of YAP reorganizes genome topology for long-term YAP target gene expression. Nat. Cell biol., 21(12):1578-1589.
2. Liu, Y., Huang, Z., Liu, H., Ji, Z., Arora, A., Cai, D., Wang, H., Liu, M., Simko, E.A., Zhang, Y., Periz, G., Liu, Z., Wang, J. (2023) DNA-initiated epigenetic cascades driven by C9orf72 hexanucleotide repeat. Neuron, 111(8):1205-21.