Imaging building blocks: molecules

Wild-type huntingtin protein (25Q) interacts with Huntingtin aggregate (94Q) in a living cell.

We develop imaging techniques to study molecular dynamics in living cells at the single-molecule level (Chen et al, 2014; Li et al, 2016; Liu et al, 2018). We apply these techniques to examine the interplay between genome organization and transcription factor dynamics (Liu et al, 2014; Xie & Dong et al, 2022; Dong et al, 2024). We also devised new methods for molecular labeling and imaging in neurons, both in intact zebrafish and neural cultures. These approaches uncovered enhanced anterograde trafficking of synaptic vesicle precursors at the axonal initial segment (AIS) (Liu et al, 2018), lipoprotein transferring from neurons to astrocytes (Ioannou et al, 2019), and differential sorting mechanisms that target two brain enriched voltage-gated sodium channels (Nav1.2 and Nav1.6) into distinct neuronal compartments (Liu et al, 2022). In addition, we analyzed live-cell dynamics of CRSPR/Cas9 (Knight et al, 2015), transcription factors during B-cell activation (Kieffer-Kwon et al, 2017), cancer inducing TF hubs (Chong et al, 2018, Hao et al, 2024), MeCP2 and its Rett syndrome mutations (Piccolo et al, 2019), 'chemigenetic' sensor (Abdelfattah et al, 2019), ecDNAs (Hung et al, 2021; Lange et al, 2022) and CRISPR/Cas12 labeled genomic loci (Yang et al, 2024) with our collaborators.

Related Publications

1. Chen, J., Zhang, Z., Li, L., Chen, B., Revyakin, A., Hajj, B., Legant, W., Dahan, M., Lionnet, T., Betzig, E., Tjian, R., and Liu, Z.@ (2014). Single-molecule dynamics of enhanceosome assembly in embryonic stem cells. Cell, 156(6):1274-1285.

2. Li, L., Liu, H., Dong, P., Li, D., Legant, W.R., Grimm, J.B., Lavis, L.D., Betzig, E., Tjian, R. @, Liu, Z.@ (2016). Real-time imaging of Huntingtin aggregates diverting target search and gene transcription. eLife, 5:e17056

3. Liu, H., Dong, P., Ioannou, M.S., Shea, J., Pasolli, A., Grimm, J., Rivlin, P., Lavis, L.D., Koyama, M., Liu, Z.@ (2018). Visualizing long-term single-molecule dynamics in vivo by stochastic protein labeling. Proc Natl Acad Sci U S A, 115(2):343-348.

4. Ioannou, M.S.@, Jackson, J., Sheu, S.H., Chang, C.L., Weigel, A.V., Liu, H., Pasolli, H.A., Xu, S., Pang, S., Hess, H.F., Lippincott-Schwartz, J.@, Liu, Z.@ (2019). Neuron-astrocyte metabolic coupling protests against activity-induced fatty acid toxicity. Cell, 177(6):1522-1535.

5. Liu, H., Wang, P.G., Pitt, G., Liu, Z.@ (2022) Direct observation of compartment-specific localization and dynamics of voltage-gated sodium channels. Journal of Neuroscience, 42(28):5482-5498. (Cover story)

Collaborations:

1. Chen, B., Legant, R.W., Wang, K., Shao, L., Milkie, D.E., Davidson, M.W., Janetopoulos, C., Wu, X.S., Hammer, J.A. 3rd, Liu, Z., English, B.P., Mimori-Kiyosue, Y., Romero, D.P., Ritter, A.T., Lippincott-Schwartz, J., Fritz-Laylin, L., Mullins, R.D., Mitchell, D.M., Bembenek, J.N., Reymann, A.C., Böhme, R., Grill, S.W., Wang, J.T., Seydoux, G., Tulu, U.S., Kiehart, D.P., Betzig, E. (2014). Lattice light sheet microscopy: imaging molecules, cells, and embryos at high spatiotemporal resolution. Science, 346(6208):1257998.

2. Knight, SC., Xie, L., Deng, W., Guglielmi, B., Bosanac, L., Witkowsky, LB., Zhang, ET., El-Beheiry, M., Dahan, M., Liu, Z.@, Doudna, JA.@, and Tjian, R.@ (2015). Dynamics of CRISPR-Cas9 genome interrogation in living cells. Science, 350(6262):823-6.

3. Grimm, J.B., English, B.P., Choi, H., Muthusamy, A.K., Mehl, B.P., Dong, P., Brown, T.A., Lippincott-Schwartz, J., Liu, Z., Lionnet, T., Lavis, L.D. (2016). Bright photoactivatable fluorophores for single-molecule imaging. Nature Methods, 13(12):985-988

4. Kieffer-Kwon, K.R., Nimura, K., Rao, S.S.P., Xu, J., Jung, S., Pekowska, A., Dose, M., Stevens, E., Mathe, E., Dong, P., Huang, S.C., Ricci, M.A., Baranello, L., Zheng, Y., Tomassoni Ardori, F., Resch, W., Stavreva, D., Nelson, S., McAndrew, M., Casellas, A., Finn, E., Gregory, C., St Hilaire, B.G., Johnson, S.M., Dubois, W., Cosma, M.P., Batchelor, E., Levens, D., Phair, R.D., Misteli, T., Tessarollo, L., Hager, G., Lakadamyali, M., Liu, Z., Floer, M., Shroff, H., Aiden, E.L., Casellas, R. (2017). Myc regulates chromatin decompaction and nuclear architecture during B cell activation. Molecular Cell, 67(4):566-78.

5. Xie, L., Torigoe, S., H., Xiao, J., Mai, D.H., Li, L., Davis, F.P., Maire-Nelly, H., Grimm, J.B., Lavis, L.D., Darzacq, X., Cattoglio, C., Liu, Z.@ and Tjian, R.@ (2017). A dynamic interplay of Klf4 enhancer elments drives naïve-pluripotency. Genes & Development, 31(17):1795-1808.

6. Chong, S., Dugast-Darzacq, C., Liu, Z., Dong, P., Dailey, G.M., Cattoglio, C., Heckert, A., Sambashiva, B., Lavis, L.D., Darzacq, X., Tjian, R. (2018). Imaging dynamic and selective low-complexity domain interactions that control gene transcription. Science, 361(6400).

7. Abdelfattah, A.S., Kawashima, T., Singh, A., Novak, O., Liu, H., Shuai, Y., Huang, Y.C., Campagnola, L., Seeman, S.C., Yu, J., Zheng, J., Grimm, J.B., Patel, R., Friedrich, J., Mensh, B.D., Paninski, L., Macklin, J.J., Murphy, G.J., Podgorski, K., Lin, B.J., Chen, T.W., Turner, G.C., Liu, Z., Koyama, M., Svoboda, K., Ahrens, M.B., Lavis, L.D., Schreiter, E.R. (2019). Bright and photostable chemigenetic indicators for extended in vivo voltage imaging. Science, 365(6454):699-704.

8. Piccolo, F.M., Liu, Z., Deng, D., Hsu, C., Stoyanova, E.I., Rao, A., Tjian, R., Neintz, N. (2019). MeCP2 nuclear dynamics in live neurons results from low and high affinity chromatin interactions. eLife, 8:e51449.

9. Grimm, J.B., Tkachuk, A.N., Xie, L., Choi, H., Mohar, B., Falco, N., Schaefer, K., Patel, R., Zheng, Q., Liu, Z., Lippincott-Schwartz, J., Brown, T.A., Lavis, L.D. (2020). A general method to optimize and functionalize red-shifted rhodamine dyes. Nature Methods, 17(8):815-821

10. Lerner, J., Gomez-Garcia, P.A., McCharhy, R.L., Liu, Z., Lakadamyali, M., Zaret, K.S. (2020). Two-parameter mobility assessments discriminate diverse regulatory factor behaviors in chromatin. Molecular Cell, 79(4):677-688.

11. Hung, K.L.*, Yost, K.E.*, Xie, L.*, Shi, Q., Helmsauer, K., Luebeck, J., Schöpflin, R., Lange, J.T., Chamorro González, R., Weiser, N.E., Chen, C., Valieva, M.E., Wong, I.T., Wu, S., Dehkordi, S.R., Duffy, C.V., Kraft, K., Tang, J., Belk, J.A., Rose, J.C., Corces, M.R., Granja, J.M., Li, R., Rajkumar, U., Friedlein, J., Bagchi, A., Satpathy, A.T., Tjian, R., Mundlos, S., Bafna, V., Henssen, A.G., Mischel, P.S., Liu, Z., Chang, H.Y. (2021) ecDNA hubs drive cooperative intermolecular oncogene expression. Nature, 600(7890):731-736.

12. Lange, J.T., Rose, J.C., Chen, C.Y., Pichugin, Y., Xie, L., Tang, J., Hung, K.L., Yost, K.E., Shi, Q., Erb, M.L., Rajkumar, U., Wu, S., Taschner-Mandl, S., Bernkopf, M., Swanton, C., Liu, Z., Huang, W., Chang, H.Y., Bafna, V., Henssen, A.G., Werner, B., Mischel, P.S. (2022) The evolutionary dynamics of extrachromosomal DNA in human cancers. Nature Genetics, 54(10):1527-1533.

13. Hao, S., Ye J.L., Goldfajn, N.B., Flores, E., Liang, J., Fuehrer, H., Demmerte, J., Lippincott-Schwartz, J., Liu, Z., Sukenik, S., Cai, D. (2024) YAP condensates are highly organized hubs. iScience, 27(6):109927.

14. Wong, V.C., Houlihan, P.R., Liu, H., Walpita, D., DeSantis, M.C., Liu, Z., O'Shea, E.K. (2024) Plasticity-induced actin polymerization in the dendritic shaft regulates intracellular AMPA receptor trafficking. Elife, 15;13:e80622.

15. Yang, L., Min, Y., Liu, Y., Gao, B., Liu, X., Huang, Y., Wang, H., Yang, L., Liu, Z., Chen, L. CRISPR-array-mediated imaging of non-repetitive and multiplex genomic loci in living cells. (2024) Nature Methods, 21(9):1646-1657.