In eukaryotic cells, DNA is hierarchically packaged into a higher order structure called chromatin. Chromatin is a dynamic structure built of smaller, more fundamental units called nucleosome, which is the target of epigenetic regulation. Nucleosomes are modified in several ways by a host of multi-subunit protein complexes. Despite the relative abundance of published structural and biochemical works on epigenetic gene regulators, most studies are limited to looking at individual subunits or even individual domains from these large multi-protein complexes and their interactions with histone tails. In the interest of gaining a better understanding the molecular mechanisms of epigenetic gene regulation, we will focus on investigating the molecular mechanisms of nucleosome assembly, modification and recognitions by the multi- protein complexes rather individual subunit. To achieve these goals, we are using an integrative structural biology approach to obtain structures for these large complexes as they interact with nucleosomes. When we obtain these structures, we will use both in vitro and in vivo approaches to study the way each complex and its subunits affect nucleosomes. We expect the outcomes of this research will provide exciting insight into the molecular mechanisms of epigenetic gene regulation. They will also help us establish a platform upon which to develop and even cure diseases caused by defects in epigenetic gene regulation.
Cryo-EM Structure of human DOT1L Bound to Nucleosome
(Jang et al., Genes & Dev. 2019)
Cryo-EM Structure of Abo1 ATPase Histone Chaperones
(Cho et al., Nature Communications. 2019)
Alzheimer’s (AD), Parkinson’s (PD), Spinocerebellar Ataxia (SCA), and Huntington’s (HD) disease are among the most common neurodegenerative diseases. HD and SCA belong to the polyglutamine (polyQ) disease family. PolyQ diseases are dominantly inherited neurodegenerative disorders that typically manifest in midlife. They include motor, psychiatric, and cognitive symptoms that lead to death 15–20 years after onset. PolyQ diseases are particularly interesting because each is caused by a CAG repeat (encoding polyglutamine) expansion in a single gene. In contrast, AD and PD can be caused by multiple genes. This suggests the polyQ diseases may be more amenable to therapeutic intervention than AD and PD. The fact that each polyQ disease has different pathological hallmarks caused by polyQ expansions in different causative protein suggests polyQ expansions alter the structure and function of the protein in which they are embedded. Then, it is this altered function that causes disease. Although the genes responsible for each of the nine polyQ diseases have been known for decades, little is known about the way the polyQ expansion affects each full-length protein. Consequently, we have no effective cures for any of these diseases. Furthermore, the physiological functions of several of the polyQ disease proteins (e.g., Huntingtin and Atrophin-1) are totally unknown. We are investigating the molecular mechanisms of polyQ diseases, focusing specifically on HD and SCA by systematically analyzing the differences between normal and disease-causing versions of each protein using an integrated structural and biochemical approach. We also collaborate to examine the implications of our findings in disease pathogenesis. This line of research will provide insights into the molecular mechanisms of polyQ-associated neurological disorders and will facilitate the development of future cures.
PolyQ expansion in Huntington's disease alters
the global structure of huntingtin
(Jung, Bae, Tamo & Kim et al., Structure 2020)
Molecular Architectures and Sociology of Life
Proteins function in complexes with other proteins. However, little is known about the complexity and diversity of protein complexes and supramolecular structures in-cell and their functions. We are investigating the complexity and diversity of supramolecular structures of proteins in-cell and their functions by comprehensive analysis of structures in cells and molecular sociology among proteins followed by functional studies utilizing utilize cryo-EM and cryo-ET