| Research Interests:
Eukaryotic DNA is packaged into an organized structure collectively referred to as chromatin. The nucleosome is the fundamental unit of chromatin and is composed of 146 base pairs of DNA wrapped around a histone H3/H4 tetramer and two histone H2A/H2B dimers. Once thought to be merely a means of folding and packaging DNA, it is now known that chromatin takes an active and dynamic role in many processes such as transcription, replication, DNA repair and recombination. For example, areas of the genome that are transcriptionally silenced are associated with highly condensed chromatin (heterochromatic) regions while expressed genes tend to be localized in more open (euchromatic) regions. Covalent modification of histone proteins, such as acetylation, phosphorylation, methylation, and ubiquitylation, can reduce the histone:DNA interaction thereby opening up heterochromatic regions as well as creating binding sites for components of the transcriptional machinery. This form of control is important for tightly regulated gene expression.
Because of the facile genetic/molecular methods that are available in the yeast Saccharomyces cerevisiae, it is an excellent model system for the elucidation of many cellular processes. As histone proteins and chromatin-dependent gene regulation are highly conserved, yeast proven to be a valuable tool in understanding the role of chromatin in the regulation of many disease processes (e.g., cancer). My current interests lie in the role of chromatin in the regulation of multidrug resistance (MDR) in opportunistic fungi, specifically, that of Candida albicans and other Candida species. Using S. cerevisiae, we have found that chromatin modifications are important in the expression of genes that encode membrane-bound cellular pumps (Pdr5 and Snq2) that are responsible for the efflux of a wide variety of toxic compounds (including the antifungals miconazole and fluconazole) out of the cell. We are now in the process of directly examining the role of these modifications in C. albicans and C. glabrata MDR.
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| Publications:
1. Lo, W.S., K.W. Henry, and S.L. Berger. Histone modification patterns during gene activation. Meth. Enzym. 377:130-153, 2004.
2. Kao, C.F., C. Hillyer, T. Tsukuda, K. Henry, S. Berger, and M.A. Osley. Rad6 plays a role in transcriptional activation through ubiquitylation of histone H2B. Genes Dev. 22:184-195, 2004.
3. Henry, K.W., A. Wyce, W.S. Lo, L.J. Duggan, N.T. Emre, C.F. Kao, M.A. Osley, and S.L. Berger. Transcriptional activation via sequential histone H2B ubiquitylation and deubiquitylation, mediated by SAGA-associated Ubp8. Genes Dev. 21:2648-2663, 2003.
4. Henry, K.W., J.T. Nickels, and T.D. Edlind. ROX1 and ERG regulation in Saccharomycescerevisiae: implications for antifungal susceptibility. Euk. Cell. 1:1041-1044, 2002.
5. Edlind, T.D., L. Smith, K.W. Henry, S.K. Katiyar, and J.T. Nickels. Antifungal activity in Saccharomyces cerevisiae is modulated by calcium signaling. Mol. Microbiol. 46:257-268, 2002.
6. Henry, K.W., and S.L. Berger. Trans-tail histone modifications: wedge or bridge? Nat. Struct. Biol. 9:565-566, 2002.
7. Edlind, T.D., K.W. Henry, K. Metera, and S.K. Katiyar. (2001) Aspergillus fumigatus CYP51 sequence: potential basis for fluconazole resistance. Med. Mycol. 39:299-302, 2001.
8. Baudry, K., E. Swain, A. Rahier, M. Germann, A. Batta, S. Rondet, S. Mandala, K.W. Henry, G.S. Tint, T.D. Edlind, M. Kurtz, and J.T. Nickels. The effect of the erg26-1 mutation on the regulation of lipid metabolism in Saccharomyces cerevisiae. J. Biol. Chem. 276:12702-12711, 2001.
9. Henry, K.W., J.T. Nickels, and T.D. Edlind. Upregulation of ERG genes in Candida species by azoles and other sterol biosynthesis inhibitors. Antimicrob. Agents Chemother. 44:2693-2700, 2000.
10. Henry, K.W., M.C. Cruz, S.K. Katiyar and T.D. Edlind. Antagonism of azole activity against Candida albicans following induction of multidrug resistance genes by selected antimicrobial agents. Antimicrob. Agents Chemother. 43:1968-1974, 1999.
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