The School of Molecular and Cellular Biology at the University of Illinois at Urbana-Champaign

The eukaryotic transcription factor NF-κB regulates a wide range of host genes that govern the inflammatory and immune responses in mammals. The NF-κB signaling pathway controls multiple key cellular processes, including programmed cell death, cell proliferation, and differentiation. NF-κB is activated by a variety of chemokines, bacteria, viruses and their products via distinct signal transduction pathways mediated by different receptors, including TNF-a receptors, Toll-like receptors, and antigen-specific T- and B-cell receptors.

The long-term goals of this laboratory are to determine how the NF-κB transcription factor complex is regulated at the molecular level and to elucidate the roles of NF-κB in inflammation, apoptosis, and tumorigenesis. In particular, we are interested in dissecting how different stimuli converge to activate NF-κB under normal and pathological conditions using a combination of biochemical, molecular, cellular, and genetic approaches.

Currently, we are interested in the role of post-transcriptional modifications of NF-κB and histones in the regulation of NF-κB signaling pathway.

1. Post-translational modifications and NF-κB activation
   While it is clear that post-translational modifications, including phosphorylation and acetylation, play critical roles in shaping the nuclear function of NF-κB, many unanswered questions remain. For example, how do these modifications regulate NF-κB in vivo? Do they contribute significantly to the NF-κB's proinflammatory or anti-apoptotic functions? Is there a "transcription factor code" generated by acetylation, phosphorylation, and other modifications? If so, does it mediate the selection of specific target genes or control the strength and duration of the nuclear action of NF-κB? Answering these questions would advance our understanding of how NF-κB is regulated and could also provide exciting new therapeutic options for manipulating NF-κB action in cancer or inflammation.
2. Chromatin remodeling and NF-κB activation
   To increase the accessibility of the cell’s transcription and replication machinery to promoters, chromatin remodeling must occur. For example, the conformation of chromatin is altered by chromatin remodeling complexes and the N-terminal tails of histones are modified by enzymes, including histone acetyltransferases and deacetylases, kinases, and methyl transferases. These enzymes play important roles in regulation of gene expression by modifying the histones and thus controlling the accessibility of chromatin by accessory regulator factors. Several of these enzymes interact with NF-κB and regulate NF-κB-dependent transactivation. However, it remains largely unknown whether and how chromatin remodeling mediates NF-κB target gene selection. How are these enzymes regulated in the NF-κB signaling pathway? Using different approaches including chromatin immunoprecipitation assays, we will identify the enzymes that are recruited to different NF-κB target genes in a stimulus-specific manner and determine how these recruitments are regulated.