Jiafu Long

Professor, Department of Biochemistry and Molecular Biology, Nankai University

Summary of my work

Epigenetics is the study of changes (e.g. DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs-associated gene silencing) in organisms caused by modification of gene expression rather than alteration of the genetic code itself. New and ongoing research is continuously uncovering the role of epigenetics in a variety of human disorders and fatal diseases. To date, various protein or protein complexes are identified in the process of establishment, maintenance, or erasing of these epigenetic changes, the mechanism(s), however, is still unclear. My lab focuses on fundamental problems in epigenetic gene regulation and disease by using combined biochemical and structural approaches, and we are also interest in structure-based protein engineering for cancer therapy application. A series interesting results have been obtained to elucidate the molecular mechanism of Elongator complex assembly involved in histone modification or Paf1 complex assembly and functional regulation, and to reveal the mechanism of SATB1 multimerization in regulation high-order chromatin structure or Hippo pathway regulating gene expression.

While at Cornell, my objective is to determine the three-dimensional structure of the inositol polyphosphate 4-phosphate (Inpp4) by using cutting-edge tools such as cryo-electron microscopy (cryo-EM). We use insect cells expression system to express and purify Inpp4 recombinant proteins and then apply biochemical assays to test its phosphate actives. Structure-inspired mutagenesis and functional analysis in cell might be helpful for us to reveal the role of Inpp4 in modulating EGFR trafficking or promoting triple-negative breast cancer.

Impacts in China

Disrupting any of the epigenetic changes can cause abnormal activation or silencing of genes. Such disruptions have been associated with cancer, syndromes involving chromosomal instabilities and mental retardation in humans from the world including China. At Cornell, I have the opportunity to use techniques of insect cells expression system and cryo-EM, and to improve my scientific thinking, which will enhance my current research in China. Results from my research interests addressed above may provide a theoretical  basis for elucidating the mechanism of epigenetic gene regulation and structural models for drug design.

Publications (representative corresponding author only):

1. Chen, G., Zhou, H.*, Liu, B., Wang, Y., Zhao, J., Giancott, F.*, Long, J.*, “A Heterotrimeric SMARCB1-SMARCC2 Subcomplex is Required for the Assembly and Tumor Suppression Function of the BAF Chromatin-remodeling Complex”, Cell Discovery, accepted, (2020).
2. Xie, Y., Zheng, M., Chu, X., Chen, Y., Xu, H., Wang, J., Zhou, H.*, Long, J.*, “Paf1 and Ctr9 subcomplex formation is essential for Paf1 complex assembly and functional regulation”,  Nat Commun., 9(1): 3795 (2018).
3. Xu, H., Lin, Z., Li, F., Diao, W., Dong, C., Zhou, H., Xie, X., Wang, Z., Shen, Y.*, Long, J.*, “Dimerization of elongator protein 1 is essential for Elongator complex assembly”, Proc. Natl. Acad. Sci. USA, 112(34): 10697-10702 (2015).
4. Li, Y., Zhou, H., Li, F., Chan, S., Lin, Z., Wei, Z., Yang, Z., Guo, F., Lim, C., Xing, W., Shen, Y., Hong, W., Long, J.*, Zhang, M.*, “Angiomotin binding-induced activation of Merlin/NF2 in the hippo signaling pathway”, Cell Res., 25(7): 801-817 (2015).
5. Dong, C., Lin, Z., Diao, W., Li, D., Chu, X., Wang, Z., Zhou, H., Xie, Z., Shen, Y.*, Long, J.*, “The Elp2 subunit is essential for Elongator assembly and functional regulation”, Structure, 23(6): 1078-1086 (2015).
6. Wang, Z., Yang, X., Guo, S., Yang, Y., Su, X-C., Shen, Y.*, Long, J.*, “Crystal structure of the Ubiquitin-like domain-CUT repeat-like tandem of special AT-rich sequence binding protein 1 (SATB1) reveals a coordinating DNA-binding mechanism”, J. Biol. Chem., 289(40): 27376-27385 (2014).
7. Chu, X., Qin, X., Xu, H., Li, L., Wang, Z., Li, F., Xie, X., Zhou, H., Shen Y.*, Long, J.*, “Structural insights into Paf1 complex assembly and histone binding”, Nucleic Acids Res., 41(22): 10619-10629 (2013).
8. Xie, X., Yang, X., Wang, Z., Zhou, H., Diao, W., Zhou, W., Long, J.*, Shen, Y.*, “Open-closed mechanism of Mint2 regulates APP metabolism”, J. Mol. Cell Biol., 5(1): 48-56 (2013).
9. Lin, Z., Zhao, W., Diao, W., Xie, X., Wang, Z., Zhang, J., Shen, Y.*, Long, J.*, “Crystal structure of Elongator subcomplex Elp4-6”, J. Biol. Chem., 287(25): 21501-21508 (2012).
10. Zhang, J., Yang, X., Wang, Z., Zhou, H., Xie, X., Shen, Y.*, Long, J.*, “Structure of an L27 domain heterotrimer from the cell polarity complex Patj/Pals1/Mals2 reveals a mutually independent L27 domain assembly mode”, J. Biol. Chem., 287(14): 11132-11140 (2012).
11. Wang, Z., Yang, X., Chu, X., Zhang, J., Zhou, H., Shen, Y.*, Long, J.*, “The structural basis for the oligomerization of the N-terminal domain of SATB1”, Nucleic Acids Res., 40(9): 4193-4202 (2012).
12. Yang, X., Xie, X., Chen, L., Zhou, H., Wang, Z., Zhao, W., Tian, R., Zhang, R., Tian, C., Long, J.*, Shen, Y.*, “Structural basis for tandem L27 domain-mediated polymerization”, FASEB J., 24(12): 4806-4815 (2010).
13. Yan, X., Zhou, H., Zhang, J., Shi, C., Xie, X., Wu, Y., Tian, C., Shen, Y.*, Long, J.*, “Molecular Mechanism of Inward Rectifier Potassium Channel 2.3 Regulation by Tax-interacting Protein-1”, J. Mol. Biol., 392(4): 967-976 (2009).
14. Zhang, J., Yan, X., Shi, C., Yang, X., Guo, Y., Tian, C., Long, J.*, Shen, Y.*, “Structural basis of b-catenin Recognition by Tax-interaction Protein-1”, J. Mol. Biol., 384(1): 255-263 (2008).