Karl W. Henry

Assistant Professor
Microbiology and Immunology
2900 Queen Lane
Philadelphia, PA 19129
Tel :(215) 991-8352
Fax: (215) 848-2271
Email: karl.henry@drexel.edu

Ph.D., 2001, Microbiology and Immunology, Medical College of Pennsylvania and Hahnemann University

Keywords:

Chromatin, yeast, histone, multidrug resistance

Research Interests

Our research is focused on the role of chromatin and chromatin modifying enzymes in the regulation of multidrug resistance and virulence-related gene expression in pathogenic fungi. While chromatin was once thought to be merely a means of condensing and packaging DNA to allow it to fit within the eukaryotic cell nucleus, it is now accepted that chromatin plays an active and dynamic role in many cellular processes such as transcription, replication, DNA repair, and recombination. Composed of 146 base pairs of DNA and eight histone proteins (an H3/H4 tetramer and two H2A/H2B dimers), the nucleosome is the fundamental unit of chromatin and is essential for proper packaging and gene regulation. Areas of the genome that are transcriptionally silenced are associated with highly condensed chromatin (heterochromatic) regions while more open (euchromatic) regions of the genomes are linked with active transcription. The covalent modification of histone proteins, such as acetylation, phosphorylation, methylation, and ubiquitylation can alter the histone:DNA interaction to open up heterochromatic regions as well as creating binding sites for downstream components of the transcriptional machinery. This form of transcriptional control is important for tightly regulated gene expression.

Because of the facile genetic and 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, S. cerevisiae has proven to be a valuable tool in understanding the role of chromatin in the regulation of many disease processes in higher organisms (e.g., cancer). 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 have extended this work into the opportunistic fungal pathogen Candida glabrata and found similar results. Furthermore, we have also identified histone modifying enzymes as having a role in the yeast-to-hyphae transition in C. albicans, perhaps the single most important opportunistic fungal pathogen. The ability of C. albicans to have several morphological forms is believed to be an important virulence factor influencing host adhesion, penetration, and immunological avoidance. Understanding the role of histone modifying enzymes in both MDR and virulence may provide key insights towards treatment of these (and other) fungal pathogens.

Selected Research Publications

T.D. Edlind, K.W. Henry, J.P. Vermitsky, M.P. Edlind, S. Raj, S.K. Katiyar. (2005) Promoter-dependent disruption of genes: simple, rapid, and specific PCR-based method with application to three different yeast. Curr. Genet. 48:117-125.
W.S. Lo, E.R. Gamache, K.W. Henry, D. Yang, L. Pillus, S.L. Berger. (2005) Activator-targeted Snf1-mediated histone H3 phosphorylation promotes TBP recruitment through distinct promoter-specific mechanisms. EMBO J. 24:997-1008.
N.C.T. Emre, K. Ingvarsdottir, A. Wyce, A. Wood, N.J. Krogan, K.W. Henry, K. Li, J.F. Greenblatt, R. Mormorstein, A. Shilatifard, S.L. Berger. (2005) Maintenance of low histone ubiquitylation by Ubp10 correlates with telomere proximal Sir2 association and gene silencing. Mol. Cell. 17:585-594.
C.F. Kao, C. Hillyer, T. Tsukuda, K. Henry, S. Berger, M.A. Osley. (2004) Rad6 plays a role in transcriptional activation through ubiquitylation of histone H2B. Genes Dev. 22:184-195.
K.W. Henry, A. Wyce, W.S. Lo, L.J. Duggan, N.T. Emre, C.F. Kao, M.A. Osley, S.L. Berger. (2003) Transcriptional activation via sequential histone H2B ubiquitylation and deubiquitylation, mediated by SAGA-associated Ubp8. Genes Dev. 21:2648-2663.
K.W. Henry, J.T. Nickels, and T.D. Edlind. (2002) ROX1 and ERG regulation in Saccharomyces cerevisiae: implications for antifungal susceptibility. Euk. Cell. 1:1041-1044.
T.D. Edlind, L. Smith, K.W. Henry, S.K. Katiyar, J.T. Nickels. (2002) Antifungal activity in Saccharomyces cerevisiae is modulated by calcium signaling. Mol. Microbiol. 46:257-268.
T.D. Edlind, K.W. Henry, K. Metera, and S.K. Katiyar. (2001) Aspergillus fumigatus CYP51 sequence: potential basis for fluconazole resistance. Med. Mycol. 39:299-302.
K. Baudry, 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. (2001) The effect of the erg26-1 mutation on the regulation of lipid metabolism in Saccharomyces cerevisiae. J. Biol. Chem. 276:12702-12711.
K.W. Henry, J.T. Nickels, and T.D. Edlind. (2000) Upregulation of ERG genes in Candida species by azoles and other sterol biosynthesis inhibitors. Antimicrob. Agents Chemother. 44:2693-2700.
K.W. Henry, M.C. Cruz, S.K. Katiyar and T.D. Edlind. (1999) Antagonism of azole activity against Candida albicans following induction of multidrug resistance genes by selected antimicrobial agents. Antimicrob. Agents Chemother. 43:1968-1974.