My lab studies the epigenetic regulation of gene expression and genomic integrity. All the activities of the Eukaryotic genome, including DNA repair, gene expression, and DNA replication are tightly regulated by packaging the DNA together with histones into chromatin and by dynamic alterations to this chromatin structure. The goal of our research is to discover novel ways in which the chromatin structure is altered during gene expression and double-strand DNA repair, and to understand how these chromatin dynamics regulate these key nuclear processes. For example, we recently showed for the first time that histones are acetylated and then deacetylated during the process of double-strand DNA repair via homologous recombination, and that failure to do so results in cell death. We have also recently discovered that the removal of histones from promoter regions is essential for transcriptional activation, while the replacement of histones onto promoter regions is essential for transcriptional repression. Our lab is now defining how these and other chromatin changes occur and the molecular mechanisms by which they regulate normal gene expression patterns and double-strand DNA repair. Our studies use a combination of molecular genetic in budding yeast, tissue culture studies, biochemistry, biophysics and structural approaches. The proteins and processes that we study are so highly conserved through eukaryotic evolution, that what we learn in the highly genetically malleable yeast system is directly relevant to the situation in humans. In addition to learning how chromatin regulates fundamental processes in the cell, our studies are helping us to understand how defects in the chromatin structure lead to gene dysfunction and genomic instability, in turn causing human aging and disease states including cancer and leukemia.
Representative Publications:
Tyler, J. K., Adams, C. R., Chen, S. –R., Kobayashi, R., Kamakaka, R. T. & Kadonaga, J. T. The RCAF complex mediates chromatin assembly during DNA replication and repair. (1999) Nature 402, 555-560.
Tyler, J. K. & Kadonaga, J.K. The dark side of chromatin remodeling: repressive effects on transcription. (1999) Cell 99, 443-446.
Tyler, J. K.*, Collins, K. A., Prasad-Sinha, J., Amiott, E., Bulger, M., Harte, P. J., Kobayashi, R. & Kadonaga, J. T. Interaction between the Drosophila CAF-1 and ASF1 chromatin assembly factors. (2001) Molecular and Cellular Biology 21, 6574-6584. *Corresponding author.
Tyler, J. K. Chromatin assembly: cooperation between histone chaperones and ATP-dependent nucleosome remodeling activities. (2002) European Journal of Biochemistry 269, 2268-2274.
Adkins, M., Howar, S. & Tyler, J. K. Chromatin disassembly mediated by the histone chaperone ASF1 is essential for transcriptional activation of the PHO5 and PHO8 genes. (2004) Molecular Cell 14, 657-66..
Ramey, C. J., Howar, S., Adkins, M., Linger, J., Spicer, J, & Tyler, J. K. Activation of the DNA damage checkpoint in yeast lacking the histone chaperone Anti-silencing function 1. (2004) Molecular and Cellular Biology 24, 10313-10327.
Adkins, M. W. & Tyler, J. K. The histone chaperone Asf1p mediates global chromatin disassembly in vivo. (2004) Journal of Biological Chemistry 279, 52069-52074.
Zabaronick, S. & Tyler, J. K. The histone chaperone anti-silencing function 1 is a global regulator of transcription independent of passage through S-phase. (2005) Molecular and Cellular Biology 25, 652-660.
Schulz, L. & Tyler, J. K. Heterochromatin focuses on senescence. (2005) Molecular Cell 17, 168-170.
Tamburini, B. & Tyler, J. K. Localized histone acetylation and deacetylation triggered by double-strand DNA repair via the homologous recombination pathway. (2005) Molecular and Cellular Biology 25, 4903-4913.
Linger, J. & Tyler, J. K. The yeast histone chaperone chromatin assembly factor 1 protects against double-strand DNA damaging agents. (2005) Genetics 171, 1513-22.
Tamburini, B., Carson, J., Adkins, M. & Tyler, J. K. Functional conservation and specialization among eukaryotic anti-silencing function 1 proteins. (2005) Eukaryotic Cell 4, 1583-90.
English, C. M., Maluf, N. K., Tripet, B., Churchill, M. E. A. & Tyler, J. K.. The histone chaperone anti-silencing function 1 binds to an H3-H4 heterodimer: a two-step mechanism for the assembly of the H3-H4 heterotetramer on DNA. (2005) Biochemistry 44, 13673-13682.
Tyler, J. K.. Chromatin Assembly Methods. (2006) Chapter 38, Cell Biology: a Laboratory Handbook. Edited by Julio E. Celis.
Schulz, L. L. & Tyler, J. K.. Localization of anti-silencing function 1 to active replication forks mediates efficient DNA replication. (2006) FASEB J 20(3):488-90.
Adkins, M. W. & Tyler, J. K.. Transcriptional activators are dispensable for transcription in the absence of Spt6-mediated chromatin reassembly of promoter regions. (2006) Molecular Cell 3, 405-416.
Tamburini, B., Carson, J., Linger, J. G. & Tyler, J. K. Dominant mutants of the Saccharomyces cerevisiae ASF1 histone chaperone bypass CAF-1 mediated nucleosome assembly and Sir protein recruitment during transcriptional silencing. (2006) Genetics 173, 599-610.
Linger, J. & Tyler, J. K. Global replication-independent histone H4 exchange in budding yeast. (2006) Eukaryotic Cell 5, 1780-7.
English, C. M., Adkins, M. W., Carson, J. J., Churchill, M. E. A. & Tyler, J. K. Structural basis for the histone chaperone activity of Asf1. (2006) Cell 127, 495-508.
Adkins, M. W., Carson, J. J., English, C. M., Ramey, J. C. & Tyler, J. K. The histone chaperone anti-silencing function 1 stimulates the acetylation of newly synthesized histone H3 in S-phase. (2007) Journal of Biological Chemistry 12, 1334-40.
Williams, S. & Tyler, J. K. Chromatin assembly and disassembly during transcription. (2007) Current Opinions in Genetics and Development 17, 88-93.
Linger, J. & Tyler, J. K. Chromatin disassembly and assembly during double-strand DNA repair. (2007) Mutation Research 618, 52-64.
Adkins, M. W., Williams, S. K., Linger, J., & Tyler, J. K. Chromatin disassembly from the PHO5 promoter is essential for the recruitment of the general transcription machinery and coactivators. (2007) Mol Cell Biol. 18, 6372-82.
Williams, S., Truong, D. & Tyler, J. K. Acetylation in the globular domain of histone H3 on lysine 56 promotes chromatin disassembly from the PHO5 promoter during transcriptional activation. (2008) Proceedings of the National Academy of Science 105, 9000-9005.
Chen, C-C., Carson, J., Feser, J., Tamburini, B., Zabaronick, S., Linger, J. & Tyler, J. K. Chromatin reassembly and acetylation of histone H3 on lysine 56 signals for the completion of double-strand DNA repair. (2008) Cell, 134, 190-201.
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