KOSEN 한인과학기술자네트워크

Research Interests

Molecular mechanisms of eukaryotic transcription factor function

Eukaryotic transcriptional control is an extremely complex process involving multiple cis-acting DNA control elements and trans-acting protein components. Chromatin unravelling is an essential component of this. The whole process is often dynamic and is regulated by external signals mediated by signal transduction cascades and protein kinases. The importance of maintaining correctly controlled transcription is emphasised by the observation that many tumours arise due to the mutation of genes encoding components of the transcription machinery or the pathways which modify their activity. My lab is studying how transcription factors function at the molecular level and how they link to cellular signaling pathways. As model systems, we are investigating members of the ETS and Forkhead transcription factor families and how these act in concert with other transcription factors and coregulators to control gene expression. Current projects:
1. Signaling to transcription factors during stem cell differentiation: Early differentiation of embryonic stem cells is driven by the MAP kinase and GSK3 signaling pathways. Little is known about how these pathways communicate with the nucleus to promote the differentiation process. We have conducted a genome-wide RNAi screen to identify novel downstream modulators of the ERK signaling response and wish to explore how these are wired into the upstream signaling pathways.
2. Control of the cell cycle by transcription factor complexes: (Nature 2006, 444, 494). We are interested in how transcription is controlled during the cell cycle in response to intra- and extra-cellular cues. One model we are using is the yeast Fkh2 forkhead transcription complex. This complex regulates genes involved in M-phase entry and progression and responds to regulatory cues elicited by the cyclin-Cdk and polo cell-cycle kinases. Further work is investigating the function of analogous mammalian forkhead proteins such as FOXM1 and FOXK2 in cell cycle control (JBC, 2010, 285, 35728).
3. Control of transcription by SUMO modification: Many transcription factors are controlled by SUMO modification and this modification often is associated with the acquisition of repressive properties. Projects in the lab are aimed at understanding how SUMOylation is regulated in response to signaling pathway activation, and the molecular mechanisms through which SUMOylation causes transcriptional repression (Mol. Cell, 2004, 13, 611). More recently, we have conducted genome-wide siRNA screens to identify potential novel regulators of the SUMO pathway.
4. Transcriptional regulatory networks: The multitude of transcriptional factors and signaling pathways in the cell and the complex nature of promoters, means that extensive regulatory networks exist for controlling gene transcription. We are using a "systems analysis" approach using a combination of in silico, microarray- and sequencing-based techniques to probe the networks controlled by transcription factors and coactivators in response to differential cellular signaling (Genome Research, 2009, 19, 1963). Incorporated into these studies, are mechanistic approaches aimed at understanding how transcription factors orchestrate changes in chromatin structure in response to signaling cues.
5. Transcriptional control modules in oesophageal cancer: Oesophageal cancer is highly prevalent and yet has poor survival rates, due to a lack of suitable treatments and poor diagnostic and prognostic markers. We are interested in how transcription factors contribute to oesophageal cancer and their relationships to signaling pathways in this context (Mol. Cancer, 2010, 9, 313). Current projects are focussed on the Plk-1-FOXM1 axis and its target gene network and its relevance to oesophagea