The packaging of genomic DNA into nucleosomes and further into higher-order chromatin fibers forms an intricate system to regulate gene activities through chromatin structure in eukaryotes. Nucleosome, the basic subunit of chromatin presents a significant physical barrier to regulatory proteins whose function relies on the access of DNA. Epigenetic mechanisms, such as histone acetylation and ATP-dependent chromatin remodeling exist in cells to overcome this barrier by creating an “open” and thus active chromatin region. Conversely, mechanisms such as DNA methylation and specific histone methylation can result in further folding of chromatin, leading to gene repression. The tight control and fine balance of these two antagonizing processes play a central role in regulating all nuclear processes such as transcription, DAN replication and repairs. Key players in these processes are known as epigenetic regulators. They are known to function as molecular switches that control the “on” and “off” state of genes, and therefore play a central role in establishing cell-type specific gene expression pattern during normal development of all multicellular organisms. Despite their great potential as drug targets for various human pathologies, we know very little about how these chromatin modulators interact with their substrates and how they are regulated at the molecular level. Our approaches include cryo-electron microscopy (EM), traditional biochemistry and various biophysical techniques. Current research in the lab focus on:

Structural dynamics and regulation of 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. Remodelers are found to be intimately involved in many nuclear transactions, such as DNA replication, DNA damage repairs, and transcription regulations. Four families of remodelers have been identified, all of which share a conserved ATPase subunit.  Using the combined techniques mentioned above, we aim to understand 1) how are chromatin remodelers regulated?  2) what are their roles in nuclear processes outside of transcription?

Regulation of chromatin by histone variants

Histone variants are nonallelic isoforms of canonical histones. Unlike canonical histones that are synthesized and incorporated during S-phase, variants deposition is replication-independent. It was discovered that histone variants play an active and indispensable role in gene regulation during multicellular organism development. The incorporation of histone variant involves removing one or more canonical histones and replace it with specific variants. This results in alterations of the biochemical composition and the physical characteristics of the nucleosome.  We are interested in understanding how the incorporation of different histone variants alter the structures and functional states of chromatin. We are also investigating how histone variants influence the activities and functions of specific epigenetic factors.