Prof. Dr. Patrick Matthias

Born 1957 Email: Patrick.matthias@fmi.ch Received his diploma in Biology from the University of Geneva (Switzerland). Performed his PhD work in the laboratory of Günter Schütz at the German Cancer Research Center in Heideleberg, working on the hormonal regulation of gene expression. Did postdoctoral research at the University of Zürich, working with Walter Schaffner on the identification and cloning cell-specific transcription factors. In 1990 went to the Whitehead Institute at MIT in Cambridge and worked with David Baltimore on the definition of a novel enhancer in the immunoglobulin locus./li> Returned 1991 to Switzerland and established his laboratory at the Friedrich Miescher Institute, focussing on transcriptional regulation in lymphocytes. Since 1997 Senior group leader at FMI. Since 2001 member of the Faculty of 1000. Since 2004 Adjunct Professor of Molecular Biology at the University of Basel. Past and current Research The research in the Matthias laboratory has been and still is largely centered on dissecting transcriptional networks in B lymphocytes. The emphasis has been mainly on understanding the regulation and function of transcription factors such as Oct-1 and Oct-2, and also their coactivator OBF-1, which was first cloned in the Matthias laboratory. Analysis in vitro and in vivo with knockout and transgenic mice defined the roles of these factors for the development and function of B lymphocytes and critical functions were identified for OBF-1 in regulating for example formation of germinal centers, or the transition between immature and mature B cells. Other transcription factors are also studied, and their interdependence is examined. For example, a novel role for OBF-1, working in concert with the chromatin regulator Aiolos, was recently identified in the developmentally regulated silencing of the lambda5 gene. In recent years, the laboratory also started to analyze the role of histone deacetylases (HDACs) and protein acetylation in lymphocytes, as well as in other settings. A major focus has been put on the class I enzymes HDAC1 & 2, as well as on HDAC6, a class II protein. While HDAC1 and -2 appear to be almost exclusively regulating chromatin, HDAC6 is mostly cytoplasmic and regulates a variety of cellular processes. Genetic models have been established to dissect the function of these genes.   Research within the Node   In the context of the Cellplasticity project we want to broadly test the role of chromatin regulators and select transcription factors for lymphoid cell development and function. For this, we have performed a detailed transcriptional profiling through multiple stages of early B cell development and have then extensively mined the data, examining in particular proteins that can contribute to genetic or epigenetic regulation, such as transcription factors or known as well as putative chromatin modifiers. By this approach we discovered that the expression of many chromatin regulators is indeed regulated through B cell development. For simplification, we grouped these genes in three categories: (i) genes that are expressed at constant level through B cell differentiation, (ii) genes that are expressed at high level early on and then become downregulated, and (iii) genes whose expression increases through B cell development. We intend to disturb this developmental regulation by overexpressing their cDNAs, or corresponding shRNAs. For this, we are establishing an efficient protocol for targeting ES cells in the Rosa26 locus with inducible expression cassettes, so that the cDNA or the shRNA RNA can be expressed as needed under hormonal control. Targeted ES cells will be used for either in vitro differentiation experiments or Rag complementation assays, and the impact of perturbing the normal expression pattern will be examined. These experiments will allow us to comparatively define the importance of genetic and epigenetic regulation for lymphoid development; in addition, it will also be possible to generate mutant mice strains from targeted ES cells when deemed appropriate.

Relevant publications:

Schubart, K., Rolink, A., Massa, S., Schubart, D., Corcoran, L. M. & Matthias, P. (2001) B cell development and immunoglobulin gene transcription in the absence of Oct-2 and OBF-1. Nature Immunology, 2, 69-74 Matthias, P. & Rolink, A. (2005) Transcriptional Networks in Developing and Mature B Cells. Nature Review in Immunology, 5, 497-508 Bartholdy, B., Du Roure, C., Bordon, A., Emslie, D., Corcoran, L. M. & Matthias, P. (2006) The ETS transcription factor Spi-B is a direct critical target of OBF-1. PNAS, 103(31):11665-70 Kwon, S. H., Zhang, Y. & Matthias, P. (2007) The deacetylase HDAC6 is a novel critical component of stress granules involved in the stress response. Genes Dev. Dec 15;21(24):3381-94 Karnowski, A., Cao, C., Matthias, G., Carotta, S., Corcoran, L. M., Martensson, I. L., Skok, J. A., & Matthias, P. (2008) Silencing and Nulcear Repositioning of the 5 Gene Locus at the Pre-B Cell Stage Requires Aiolos and OBF-1. PLoS ONE, 3(10):e3568. Epub 2008 Oct 30. Bordon, A., Bosco, N., Du Roure, C., Bartholdy, B., Kohler, H., Matthias, G., Rolink, A. G. & Matthias, P. (2008) Enforced Expression of the Transcriptional Coactivator OBF1 Impairs B Cell Differentiation at the Earliest Stage of Development. PLoS ONE, 3(12):e4007. Epub 2008 Dec 23