Gene Expression and Chromosome Dynamics

My group focuses on two areas:

First, we explore the role of nuclear pore complexes (NPCs) in genome regulation. Interphase chromosomes are not randomly spread throughout the nucleus but are fairly well organized, with different gene loci found in different regions of the nucleus. At the same time chromatin can undergo extensive motion. In fact, some inducible genes dramatically change nuclear positions depending on whether they are active or not. A fascinating new line of research suggests that activated genes can become hooked to nuclear pores – large transport channels, which protrude into the nuclear interior with a basket-like structure. According to this view, NPCs serve as anchors for the gene expression machineries and play a role in tuning gene activities. We would like to understand which factors mediate chromatin-NPC interactions, how these links are formed and broken and how they contribute mechanistically to transcription, RNA processing and export. Ultimately, our goal is to unravel basic principles of how nuclear architecture determines cellular function.
 

NPCs and proteins of the inner nuclear membrane partition the genome into areas of silent (yellow) and active chromatin (green). Gene-NPC interactions require various adaptors including the SAGA histone acetyltransferase (HAT) (Köhler & Hurt, Mol Cell, 2010)
 
 

Second, we investigate how ubiquitin signaling controls gene expression. While ubiquitin is well-known for tagging proteins for destruction by the proteasome, its role in regulating chromatin is far less understood. We are particularly interested in the enzymatic toolkit for histone ubiquitination (ligases & deubiquitinases). When appended to histones ubiquitin can function as a reversible molecular switch to regulate transcription, gene silencing and DNA repair. Recently, we have determined the structure of a histone deubiquitinase together with our collaborators and uncovered its sophisticated activation mechanism. Intriguingly, the Ubp8 deubiquitinase forms a protein module with three co-factors, which act in concert to assemble the module, shape the catalytic center and recognize the substrate. The deubiquitinase module is part of SAGA, a multifunctional transcription co-activator. Our studies serve as a paradigm to explain how a deubiquitinase is switched on at the right time and place inside the cell. In addition, we aim to discover novel ubiquitin functions related to RNA and chromatin biology.
 

Multi-step activation and structure of a Ubiquitin Pac-Man (Köhler et al., Cell, 2010)