Transcription Mechanism and Drug Discovery
The Zhou Laboratory focuses on unraveling the basic molecular mechanisms of chromatin-mediated gene transcription, essential for defining cell types and implicated in diseases. Dr. Zhou and colleagues study the structure-function and regulatory mechanisms of histone modifying enzymes (writers and erasers) and histone readers in gene transcription. Using a structural mechanism-guided strategy, they design chemical compounds to selectively modulate cell-type specific gene transcription. Notable contributions include the seminal discovery of the bromodomain as the first histone reader for acetyl-lysine recognition (Dhalluin et al., 1999) and revealing how gene regulatory proteins utilize combinatorial binding of modified histones to direct transcription (Zeng et al., 2010). Recent research provided unequivocal evidence for the influential ‘histone code’ hypothesis, illustrating how specific chemical modifications of a single histone residue (H3K27) dictate distinct gene transcription outcomes (Liu et al., 2023). Dr. Zhou’s pioneering work on chemical modulation of bromodomain/acetyl-lysine binding for disease treatment (Zeng et al., 2005) opened the field of bromodomain drug discovery pursued by the pharmaceutical industry.
Selected Publications
Dhalluin, C., Carlson, J., Zeng, L., He, C., Aggarwal, A.K., & Zhou, M.-M. (1999) Structure and Ligand of a Histone Acetyltransferase Bromodomain. Nature 399(6735): 491-496.
Zeng, L., Li, J., Muller, M., Yan, S., Mujtaba, S., Pan, C., Wang, Z., & Zhou, M.-M. (2005) Selective Small Molecules Blocking HIV-1 Tat and Coactivator PCAF Association. Journal of Am. Chem. Soc. 127(8): 2376-2377.
Zeng, L., Zhang, Q., Li, S.D., Plotnikov, A.N., Walsh, M.J., & Zhou, M.-M. (2010) Mechanism and Regulation of Acetylated Histone Binding of the Tandem PHD Finger of DPF3b. Nature 466(7303): 258-62.
Yap, K.L., Li, S., Munoz-Cabello, A.M., Raguz, S., Zeng, L., Mujtaba, S., Gil, J., Walsh, W.J., & Zhou, M.-M. (2010) Molecular Interplay of the Non-coding RNA ANRIL and Methylated Histone H3 Lysine 27 by Polycomb CBX7 in Transcriptional Silencing of INK4a. Molecular Cell 38(5): 662-674.
Shi, J., Wang, Y., Zeng, L., Wu, Y., Deng, J., Zhang, Q., Dong, C., Li, J., Rusinova, E., Zhang, G., Wang, C., Zhu, H., Evers, B.M., Zhou, M.-M., & Zhou, B.P. (2014) Disrupting the Interaction of BRD4 with Diacetylated Twist Suppresses Tumorigenesis in Basal-like Breast Cancer. Cancer Cell 25(2): 210-225.
Yu, D., Liang, Y., Kim, C., Jaganathan, A., Ji, D., Han, X., Yang, X., Jia, Y., Gu, R., Wang, C., Zhang, Q., Cheung, K.L., Zhou, M.-M., & Zeng, L. (2023) Structural Mechanism of BRD4-NUT and p300 Bipartite Interactions in Propagating Aberrant Gene Transcription in Chromatin in NUT Carcinoma. Nature Commun. 14(1): 378.
Liu, N., Konuma, K., Sharma, R., Wang, D., Zhao, N., Cao, L.L., Ju, Y., Liu, D., Wang, Shui, Bosch, A., Sun, Y.F., Zhang, S., Ji, D.L., Nagatoishi, S., Suzuki, N., Kikuchi, M., Wakamori, M., Zhao, C.C., Ren, C.Y., Zhou, T.J.C., Xu. Y.Y., Meslamani, J., Fu, S.B., Umehara, T., Tsumoto, K., Akashi, S., Zeng, L., Roeder, R.G., Walsh, M.J., Zhang, Q., & Zhou, M.-M. (2023) Histone H3 Lysine 27 Crotonylation Mediates Gene Transcriptional Repression in Chromatin. Molecular Cell 83(13): 2206-2221.
