Postdoctoral, Harvard Medical School, MA
Ph.D., Albert Einstein College of Medicine, NY
B. Sc., Sun Yat-Sen University, China
Epigenetic refers to heritable changes in gene expressions that do not involve alteration of DNA sequence. Epigenetic mechanisms such as histone post-translational modification, ATP-dependent chromatin remodeling, and histone variance play central role in determining when and where genes are turned on and off in normal development and in diseases. The precision of these events relies on the proper functions of key players in these epigenetic processes. These epigenetic factors usually exist as multi-subunit protein complexes that directly or indirectly modulate the chromatin structure to achieve downstream affects. It is not surprising that their deregulation or mutations are linked to many forms of cancers. Of particular interest to us are the ATP-dependent chromatin remodelers and the Polycomb (PcG) Repressive Complexes. In general, PcG proteins inhibit transcription by maintaining a repressive chromatin structure, while ATP-dependent chromatin remodelers enhance transcription by generating a permissive chromatin structure. We are interested in understanding the structure-function relationship of these complexes. By using a combination of single-particle cryo-electron microscopy (cryo-EM) and various biochemical and biophysical methods, we aim to gain molecular insights into the mechanism of how these sophisticated machineries function in normal development and in disease.
Structural dynamics and regulation of INO80 ATP-dependent chromatin remodelers
ATP-dependent chromatin remodelers are multi-subunit protein complexes that use energy from ATP hydrolysis to disrupt DNA-histone contacts and to mobilize nucleosomes. They are transcriptional activators that have important functions in regulating gene expression, DNA replication and repairs. Dysregulation of some remodelers are linked to various cancers. There are four families of remodelers, the SWI/SNF, ISWI, Mi-2/CHD and INO80/ SWR1 families. All remodelers contain a DNA-dependent ATPase subunit. Our previous studies indicate that INO80 is capable of large-scale, regulated conformational changes that are linked to its nucleosome binding and enzymatic activity. To better understand this structure-function relationship, we will use single-particle cryo-EM to determine the structures of INO80 at different functional states and the INO80-nucleosome complex. We aim to dissect the detail mechanism of how INO80 is regulated and the mechanism of INO80-mediated chromatin remodeling.
Structural basis of gene repression by Polycomb Repressive Complexes
PcG proteins carry the opposite function compared to the ATP-dependent chromatin remodelers. They have well-established roles in silencing important developmental genes. They are shown to be essential for maintaining stem cell pluripotency and are frequently found deregulated or mutated in various cancers. However, the underlying mechanism of PcG-mediated gene silencing is elusive. PcG proteins form two main complexes, PRC1 (Polycomb Repressive Complex 1) and PRC2. We will use a similar strategy described above to address the following questions: 1) how is PRC2 regulated? 2) What is the mechanism of PRC2-mediated gene silencing?
For a complete list of current publications please click HERE.
Hunziker M, Barandun J, Petfalski E, Tan D, Delan-Forino C, Molloy KR, Kim KH, Dunn-Davies H, Shi Y, Chaker-Margot M, Chait BT, Walz T, Tollervey D, Klinge S. (2016) UtpA and UtpB chaperone nascent pre-ribosomal RNA and U3 snoRNA to initiate eukaryotic ribosome assembly. Nature Communication 7: 12090.
Tan D*, Blok NB*, Rapoport TA, Walz T. (2015) Structures of the double-ring AAA ATPase Pex1/Pex6 involved in peroxisome biogenesis. FEBS Journal. 283(6): 986-92. (* denotes equal contribution)
Blok NB*, Tan D*, Wang RY*, Penczek PA, Baker D, DiMaio F, Rapoport TA, Walz T. (2015) Unique double-ring structure of the peroxisomal Pex1/Pex6 ATPase complex revealed by cryo-electron microscopy. Proc Natl Acad Sci U S A.112, E4017–4025 (* denotes equal contribution)
Watanabe S*, Tan D*, Lakshminarasimhan M, Washburn MP, Hong EJ, Walz T, Peterson CL. (2015) Structural analyses of the chromatin remodelling enzymes INO80-C and SWR-C. Nature Communication 6:7108 (* denotes equal contribution)
Wang J, Tan D, Cai Y, Reinisch KM, Walz T, Ferro-Novick S. (2014) A requirement for ER-derived COPII vesicles in phagophore initiation. Autophagy 10(4): 708-709.
Tan D*, Cai Y*, Wang J, Zhang J, Menon S, Chou HT, Ferro-Novick S, Reinisch KM, Walz T. (2013) The EM structure of the TRAPPIII complex leads to the identification of a requirement for COPII vesicles on the macroautophagy pathway. Proc Natl Acad Sci U S A 110(48): 19432-19437. (* denotes equal contribution)
Asenjo AB, Chatterjee C, Tan D, Depaoli V, Rice WJ, Diaz-Avalos R, Silvestry M, Sosa H. (2013) Structural model for tubulin recognition and deformation by Kinesin-13 microtubule depolymerases. Cell Rep 3(3): 759-68.
Rath U, Rogers GC, Tan D, Gomez-Ferreria M, Buster DW, Sosa HJ, and Sharp DJ (2009) The Drosophila kinesin-13, KLP59D, impacts Pacman- and Flux-based chromosome movement. Mol. Biol. Of Cell 20(22): 4696-705.
Mennella V, Tan DY, Buster DW, Asenjo A, Sosa HJ, and Sharp DJ (2009) Motor domain phosphorylation and regulation of the Drosophila kinesin 13, KLP10A. J. Cell Biol. 186(4): 481-90.
Tan D, Rice WJ, and Sosa HJ, (2008) Structure of the Kinesin-13-microtubule ring complex. Structure. 16(11): 1723-1729.
Tan D, Asenjo AB, Mennella V, Sharp DJ, and Sosa H. (2006) Kinesin-13s form rings around microtubules. J. Cell Biol. 175(1): 25-31. (Cover Story)
Zhang Q, Cui J, Huang X, Lin W, Tan DY, Xu JW, Yang YF, Zhang JQ, Zhang X, Li H, Zheng HY, Chen QX, Yan XG, Zheng K, Wan ZY, Huang JC. (2003) Morphology and Morphogenesis of Severe Acute Respiratory Syndrome (SARS)-associated Virus. Acta Biochimica ET Biophysica sinica. 35(6): 587-591.
Jian Cheng Lu
Undergraduate, Biochemistry Major (’18)
Abu Nahiyaan Navid
Undergraduate, Pharmacology Major (’18)
Undergraduate, Biology Major (’18)