Michael J. Klemsz, Ph.D.
Associate Professor of Microbiology and Immunology
Summary of the focus of the research of Dr. Klemsz
My laboratory has two main areas of focus. In the first, we are studying how chromatin structure regulates the expression of the PU.1 gene. PU.1 is an ETS-domain transcription factor family member, PU.1. Knockout studies have shown that this factor is essential for the development of most blood cell lineages, including cells where PU.1 is normally not expressed. In contrast, over-expression of PU.1, following viral integration in erythroblasts, can result in the development of mouse erythroleukemia. Recent results suggest that the tissue-specific expression of PU.1 is controlled at the level of DNA methylation and chromatin structure. We have extended these studies to look at the role of histone modifications in regulating the expression of PU.1. These results showed that increased acetylation, following the inhibition of histone deacetylase (HDAC) activity, resulted in the loss of PU.1 expression. Although the current paradigm suggests increased acetylation would open chromatin structure and increase gene expression, the PU.1 gene falls into a category that requires a balance in the levels of acetylation by lowering acetylation levels through the recruitment of HDACs. We are now extending these studies by using chromatin immunoprecipitation and other techniques to show how and when changes occur in the patterns of histone acetylation and methylation on the PU.1 locus that may regulate its expression during the development of different lineages. The second area of focus began as studies on the regulation of TAP gene expression in macrophages. The Tap-1 and Tap-2 genes encode proteins which form a heterodimer that functions as a peptide transporter. The expression and function of these genes are required for the presentation of antigens in the context of MHC class I proteins. Recent results have shown that distinct signaling cascades from interferon-gamma and bacterial products combine as phosphorylation events on the STAT1 transcription factor. The result is synergistic increases in Tap-1 gene expression in macrophages as compared to signaling through either pathway alone. The goal of both areas of research is to understand how gene expression is controlled in the cells of the immune system and how the improper regulation of individual genes results in disease.
- Cramer, L.A., Nelson, S.L. and Klemsz, M.J. (2000) Synergistic induction of the Tap-1 gene by IFN-g and LPS in macrophages is regulated by STAT 1. J. Immunol. 165:3190-3197.
- Anderson, K.L., Nelson, S.L., Perkin, H.B., Smith, K.A., Klemsz, M.J. and Torbett, B.E. (2001) PU.1 regulates the expression of CD45 and src family kinases exclusively in myeloid cells. J. Biol. Chem. 276:7637-7642.
- Li, Y., Okuno, Y., Zhang, P., Chen, H-m., Radomska, H.S., Klemsz, M.J., McKercher, S.R., Maki, R.A. and Tenen, D.G. (2001) Regulation of the PU.1 gene by distal elements. Blood, 98:2958-2965.
- Laribee, R.N. and Klemsz, M.J. (2001) Loss of PU.1 expression following inhibition of histone deacetylases. J. Immunol, 167:5160-5166.
- Klemsz, M.J. (2002) Sequence your own. The Scientist 16:13. (Letter to the Editor).
- Throm, S.L., and Klemsz, M.J. (2003) PU.1 regulates glutathione peroxidase expression in neutrophils. J. Leukoc. Biol. 74:111-117.
- B.A. 1982, University of Colorado at Boulder
- Ph.D. 1987, University of Colorado Health Sciences Center and National Jewish Center for Immunology and Respiratory Medicine
- Postdoctoral, 1987-1991, La Jolla Cancer Research Foundation