Research Focus  

One area of our research centers on the mechanisms of eukaryotic gene regulation, including the molecular basis of signal transduction, transcription regulation and epigenetic control of chromosome structure. Specific projects in this area include structural and functional studies of NFAT, MEF2, FOXP3, and several transcription factors implicated in stem cell pluripotency and lineage control. Another area of research focuses on the structure and function of nicotinic acetylcholine receptors (nAChR) and other ligand-gated ion channels (LGICs) in neuronal signaling. We use X-ray crystallography and other biochemical methods to characterize molecular complexes of interest. Based on the structures, we use mutagenesis to further analyze the functions of these complexes in vitro and in vivo.

An important aspect of our research is to combine structural biology and chemical design to study the function of bio-macromolecular complexes. We seek to develop new biochemical techniques and cell permeable small molecules for studying the function of protein complexes in vivo. The broad goal of our studies is to understand how protein-protein interactions control the specificity of biological processes inside cells. Through this knowledge we hope to gain the ability to control specific protein-protein interactions for developing research tools and therapeutic drugs.

Images of Research Highlights  

Combinatorial gene regulation by the assembly of distinct NFAT Complexes

We have been carrying out systematic structural and functional studies of distinct NFAT complexes in collaboration with Dr. Anjana Rao¡'s lab at Harvard Medical School. These studies have shown that NFAT and the forkhead transcription factor FOXP3 bind DNA cooperatively to regulate the function of regulatory T cells (Cell 126, 375-387, 2006; Immunity 34, 479, 2011). We have previously shown that NFAT controls effector immune responses by forming cooperative NFAT/Fos-Jun/DNA complexes at regulatory elements of activation-associated genes (Nature 392, 42-48, 1998). Thus, by switching transcriptional partners, NFAT converts the acute T cell activation program into the suppressor program of regulatory T cells.

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Crystal Structure of the NFAT5 (TonEBP) bound to DNA
The butterfly-like structure of the NFAT5 dimer bears a strong resemblance to NF-kappaB, a well-known transcription factor in stress responses. The structural similarity provides a direct link between NFAT and the classical Rel/ NF-kappaB proteins. The two NFAT5 monomers contact each other on opposite sides of the DNA, presenting the first example of DNA encirclement by a sequence-specific transcription factor. This work has been published in Nature Structural Biology (Nature Structural Biology 9, 90-4, 2002). Our follow-up studies further demonstrate the structural and functional connections between NFAT and NF-kappaB ( (Nature Structural Biology 10, 800-806, 2003; Structure 16, p684-94, 2008; J. Mol. Biol. 393, 98-112, 2009). Another important finding form these studies is that subtle sequece variations in the binding sites of transcirption factors can affect the structure of the DNA-bound proteins ( (Nature Structural Biology 10, 800-806, 2003) and cellular regulation (Science 324, 407-410, 2009)

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Sequence-specific recruitment of transcription co-regulators by MEF2 bound to DNA

This study provides the first atomic view of the recruitment of a transcriptional co-repressor (Cabin1) by a DNA-bound, sequence-specific transcription factor MEF2. The structure of the Cabin1/MEF2/DNA complex provides a framework for further studying the recruiting mechanism of class II histone deacetylases (HDACs) and transcription coactivator p300 by MEF2 in muscle and neuronal cells. Both class II HDAC and p300 are key regulator of cardiac gene expression in heart. This work has been published (Nature 422, 70-4, 2003). Our follow-up studies established a detailed model by which MEF2 recruit class IIa HDACs (J. Mol. Biol. 345, 91-102, 2005; PNAS 104, 4279, 2007) and CBP/p300 (Nucleic Acid Research 39, 4464, 2011). MEF2 controls epigenetic equilibrium through signal-dependent recruitment of HDAC and HAT complexes. Disruption of this equilibrium by genetic manipulations induces deregulation of functions in animal models that mimic many human diseases, including cardiac hypertrophy, cancer, immune disorders, and neurodegeneerative diseases. Mutations and deregulation of MEF2 and its associateds factors such as CBP/p300 and class IIa HDACs have been directly linked to human diseases. Based on our extensive structure and function studies, we are developing small molecule drugs to treat these chronicle diseases by restoring the epigenetic balance mediated by MEF2 and its complexes.

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DNA bridging by Transcription Factors and Studies of the 3D Structures of the Human Genome
In our systematic structural studies of higher-order transcription complexes, we found that many transcription factors, especially those implicated in lineage control during cellular differentiation, can bind two DNA molecules in parallel (Structure 14, p159-66, 2006). We have verified this DNA-bridging mode by several transcription factors using a novel in-gel FRET method (Immunity 34, 479, 2011). Based on these studies and other data, we propose that one mechanism to control epigenetic expression pattern of a given cell is through specific folding of the 3D structure of the genome by transcription factors (TF) that control the given lineage. To test this hypothesis, we developed a tethered conformation capture (TCC) method to measure the binary contacts between genomic loci throughout the genome (US Patent 8,076,070, Filed on Aug. 6, 2008, issued Dec. 13, 2011; US patent application 20110287947, Filed on May 18, 2010, pending). In collaboration with Dr. Frank Alber's lab, we analyzed the 3D structures of the genome of a human cell line using a population-based approach. These studies establish a novel approach to studying the 3D structures of human genome and pave the way for future studies to relate the 3D structures of the human genome to cellular functions (Nature Biotechnology, Jan, 2012).

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Structural studies of nicotinic acetylcholine receptors

A model of sugar-mediated gating mechanism of nicotinic receptors
One component of the nicotinic acetylcholine receptor (nAChR) pentamer, the alpha1 subunit, is highlighted in red (depicted in ribbon). Other subunits are colored in gray (two are visible in this view). When nicotine binds to a site on nAChR (indicated by arrow #1), which is occupied by a snake toxin (alpha-bungarotoxin, colored in yellow) in this structure, the surrounding protein structure contracts. This contraction will pull the sugar chain upward (depicted in clustered spheres, arrow #2). The other end of the sugar chain is attached to a loop (a.k.a. Cys-loop) engaged with the membrane helices (referred to as the hinge in the figure, arrow #3). The upward move of the sugar chain, which is facilitated by buried water molecules (blue spheres between the two beta sheets), would trigger motions of the trans-membrane helices and the opening of the ion gate (arrow #4). The ions (green spheres) will subsequently flow from outside of the cell to the inside, thus completing a step of chemical transmission of the electrical signal between neurons or between neurons and their target cells (Nature Neuroscience 10, 953, 2007; Channels 1, p1-4, 2007; J. Physiology 588, 557-564, 2010). Our continued studies suggest that the sugar's role in different nAChR subtypes may differ in details but its overall contribution to ligand binding and signal transduction seem to be conserved (Nature Neuroscience, 14 (10), 1253-1259, 2011). Similarly, the unusual internal packing observed in nAChR alpha1 also seems to be a common feature evolved for the allosteric function of the Cys-loop receptor (J. Biol. Chem., 286, 3658, 2010). These studies have important implications for drug design (Journal of Biomolecular Structure & Dynamics, 28, 5, 2011)

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