Professional Education

  • Doctor of Philosophy, Pennsylvania State University (2015)
  • Bachelor of Chemistry, University of Science and Technology of China (2008)

Stanford Advisors

All Publications

  • Single-molecule fluorescence spectroscopy to probe structural dynamics of a macromolecular complex at a sub-nm and sub-ms resolution Wei, S., Kim, J., Lee, J., Lee, T. AMER CHEMICAL SOC. 2017
  • Chromatin structure-dependent conformations of the H1 CTD. Nucleic acids research Fang, H., Wei, S., Lee, T., Hayes, J. J. 2016; 44 (19): 9131-9141


    Linker histones are an integral component of chromatin but how these proteins promote assembly of chromatin fibers and higher order structures and regulate gene expression remains an open question. Using Förster resonance energy transfer (FRET) approaches we find that association of a linker histone with oligonucleosomal arrays induces condensation of the intrinsically disordered H1 CTD in a manner consistent with adoption of a defined fold or ensemble of folds in the bound state. However, H1 CTD structure when bound to nucleosomes in arrays is distinct from that induced upon H1 association with mononucleosomes or bare double stranded DNA. Moreover, the H1 CTD becomes more condensed upon condensation of extended nucleosome arrays to the contacting zig-zag form found in moderate salts, but does not detectably change during folding to fully compacted chromatin fibers. We provide evidence that linker DNA conformation is a key determinant of H1 CTD structure and that constraints imposed by neighboring nucleosomes cause linker DNAs to adopt distinct trajectories in oligonucleosomes compared to H1-bound mononucleosomes. Finally, inter-molecular FRET between H1s within fully condensed nucleosome arrays suggests a regular spatial arrangement for the H1 CTD within the 30 nm chromatin fiber.

    View details for PubMedID 27365050

  • Single-Molecule Observation Reveals Spontaneous Protein Dynamics in the Nucleosome JOURNAL OF PHYSICAL CHEMISTRY B Kim, J., Wei, S., Lee, J., Yue, H., Lee, T. 2016; 120 (34): 8925-8931


    Structural dynamics of a protein molecule is often critical to its function. Single-molecule methods provide efficient ways to investigate protein dynamics, although it is very challenging to achieve a millisecond or higher temporal resolution. Here we report spontaneous structural dynamics of the histone protein core in the nucleosome based on a single-molecule method that can reveal submillisecond dynamics by combining maximum likelihood estimation and fluorescence correlation spectroscopy. The nucleosome, comprising ∼147 bp DNA and an octameric histone protein core consisting of H2A, H2B, H3, and H4, is the fundamental packing unit of the eukaryotic genome. The nucleosome imposes a physical barrier that should be overcome during various DNA-templated processes. Structural fluctuation of the nucleosome in the histone core has been hypothesized to be required for nucleosome disassembly but has yet to be directly probed. Our results indicate that at 100 mM NaCl the histone H2A-H2B dimer dissociates from the histone core transiently once every 3.6 ± 0.6 ms and returns to its position within 2.0 ± 0.3 ms. We also found that the motion is facilitated upon H3K56 acetylation and inhibited upon replacing H2A with H2A.Z. These results provide the first direct examples of how a localized post-translational modification or an epigenetic variation affects the kinetic and thermodynamic stabilities of a macromolecular protein complex, which may directly contribute to its functions.

    View details for DOI 10.1021/acs.jpcb.6b06235

    View details for Web of Science ID 000382596700018

    View details for PubMedID 27487198

  • Single-Molecule Studies of the Linker Histone H1 Binding to DNA and the Nucleosome BIOCHEMISTRY Yue, H., Fang, H., Wei, S., Hayes, J. J., Lee, T. 2016; 55 (14): 2069-2077


    Linker histone H1 regulates chromatin structure and gene expression. Investigating the dynamics and stoichiometry of binding of H1 to DNA and the nucleosome is crucial to elucidating its functions. Because of the abundant positive charges and the strong self-affinity of H1, quantitative in vitro studies of its binding to DNA and the nucleosome have generated results that vary widely and, therefore, should be interpreted in a system specific manner. We sought to overcome this limitation by developing a specially passivated microscope slide surface to monitor binding of H1 to DNA and the nucleosome at a single-molecule level. According to our measurements, the stoichiometry of binding of H1 to DNA and the nucleosome is very heterogeneous with a wide distribution whose averages are in reasonable agreement with previously published values. Our study also revealed that H1 does not dissociate from DNA or the nucleosome on a time scale of tens of minutes. We found that histone chaperone Nap1 readily dissociates H1 from DNA and superstoichiometrically bound H1 from the nucleosome, supporting a hypothesis whereby histone chaperones contribute to the regulation of the H1 profile in chromatin.

    View details for DOI 10.1021/acs.biochem.5b01247

    View details for Web of Science ID 000374197100002

    View details for PubMedID 27010485

  • A novel hybrid single molecule approach reveals spontaneous DNA motion in the nucleosome NUCLEIC ACIDS RESEARCH Wei, S., Falk, S. J., Black, B. E., Lee, T. 2015; 43 (17): E111-U48


    Structural dynamics of nucleic acid and protein is an important physical basis of their functions. These motions are often very difficult to synchronize and too fast to be clearly resolved with the currently available single molecule methods. Here we demonstrate a novel hybrid single molecule approach combining stochastic data analysis with fluorescence correlation that enables investigations of sub-ms unsynchronized structural dynamics of macromolecules. Based on the method, we report the first direct evidence of spontaneous DNA motions at the nucleosome termini. The nucleosome, comprising DNA and a histone core, is the fundamental packing unit of eukaryotic genes that must be accessed during various genome transactions. Spontaneous DNA opening at the nucleosome termini has long been hypothesized to enable gene access in the nucleosome, but has yet to be directly observed. Our approach reveals that DNA termini in the nucleosome open and close repeatedly at 0.1-1 ms(-1). The kinetics depends on salt concentration and DNA-histone interactions but not much on DNA sequence, suggesting that this dynamics is universal and imposes the kinetic limit to gene access. These results clearly demonstrate that our method provides an efficient and robust means to investigate unsynchronized structural changes of DNA at a sub-ms time resolution.

    View details for DOI 10.1093/nar/gkv549

    View details for Web of Science ID 000366404600005

    View details for PubMedID 26013809

  • Sumoylated Human Histone H4 Prevents Chromatin Compaction by Inhibiting Long-range Internucleosomal Interactions JOURNAL OF BIOLOGICAL CHEMISTRY Dhall, A., Wei, S., Fierz, B., Woodcock, C. L., Lee, T., Chatterjee, C. 2014; 289 (49): 33827-33837


    The structure of eukaryotic chromatin directly influences gene function, and is regulated by chemical modifications of the core histone proteins. Modification of the human histone H4 N-terminal tail region by the small ubiquitin-like modifier protein, SUMO-3, is associated with transcription repression. However, the direct effect of sumoylation on chromatin structure and function remains unknown. Therefore, we employed a disulfide-directed strategy to generate H4 homogenously and site-specifically sumoylated at Lys-12 (suH4ss). Chromatin compaction and oligomerization assays with nucleosomal arrays containing suH4ss established that SUMO-3 inhibits array folding and higher order oligomerization, which underlie chromatin fiber formation. Moreover, the effect of sumoylation differed from that of acetylation, and could be recapitulated with the structurally similar protein ubiquitin. Mechanistic studies at the level of single nucleosomes revealed that, unlike acetylation, the effect of SUMO-3 arises from the attenuation of long-range internucleosomal interactions more than from the destabilization of a compacted dinucleosome state. Altogether, our results present the first insight on the direct structural effects of histone H4 sumoylation and reveal a novel mechanism by which SUMO-3 inhibits chromatin compaction.

    View details for DOI 10.1074/jbc.M114.591644

    View details for Web of Science ID 000346077600010

    View details for PubMedID 25294883

  • Charge transfer and retention in directly coupled Au-CdSe nanohybrids NANO RESEARCH Gao, B., Lin, Y., Wei, S., Zeng, J., Liao, Y., Chen, L., Goldfeld, D., Wang, X., Luo, Y., Dong, Z., Hou, J. 2012; 5 (2): 88-98
  • Effects of Histone Acetylation by Piccolo NuA4 on the Structure of a Nucleosome and the Interactions between Two Nucleosomes JOURNAL OF BIOLOGICAL CHEMISTRY Lee, J. Y., Wei, S., Lee, T. 2011; 286 (13): 11099-11109


    We characterized the effect of histone acetylation on the structure of a nucleosome and the interactions between two nucleosomes. In this study, nucleosomes reconstituted with the Selex "Widom 601" sequence were acetylated with the Piccolo NuA4 complex, which acetylates mainly H4 N-terminal tail lysine residues and some H2A/H3 N-terminal tail lysine residues. Upon the acetylation, we observed directional unwrapping of nucleosomal DNA that accompanies topology change of the DNA. Interactions between two nucleosomes in solution were also monitored to discover multiple transient dinucleosomal states that can be categorized to short-lived and long-lived (∼1 s) states. The formation of dinucleosomes is strongly Mg(2+)-dependent, and unacetylated nucleosomes favor the formation of long-lived dinucleosomes 4-fold as much as the acetylated ones. These results suggest that the acetylation of histones by Piccolo NuA4 disturbs not only the structure of a nucleosome but also the interactions between two nucleosomes. Lastly, we suggest a structural model for a stable dinucleosomal state where the two nucleosomes are separated by ∼2 nm face-to-face and rotated by 34° with respect to each other.

    View details for DOI 10.1074/jbc.M110.192047

    View details for Web of Science ID 000288797100021

    View details for PubMedID 21282115

  • DNA Methylation Increases Nucleosome Compaction and Rigidity JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Choy, J. S., Wei, S., Lee, J. Y., Tan, S., Chu, S., Lee, T. 2010; 132 (6): 1782-?


    Cytosine methylation on CpG dinucleotides is an essential epigenetic modification in eukaryotes. How DNA methylation modulates nucleosome structure and dynamics has been a long-standing question. We implemented a single-molecule method to monitor the effects of DNA methylation on the structure and dynamics of mononucleosomes. Our studies show that DNA methylation induces a more compact and rigid nucleosome structure, providing a physical basis for how DNA methylation might contribute to regulating chromatin structure.

    View details for DOI 10.1021/ja910264z

    View details for Web of Science ID 000275085000025

    View details for PubMedID 20095602

    View details for PubMedCentralID PMC4167393

  • Fluorescence decay of quasimonolayered porphyrins near a metal surface separated by short-chain alkanethiols APPLIED PHYSICS LETTERS Zhang, X., Chen, L., Lv, P., Gao, H., Wei, S., Dong, Z., Hou, J. G. 2008; 92 (22)

    View details for DOI 10.1063/1.2938861

    View details for Web of Science ID 000256527900086