Molecular genetics of gene silencing in Saccharomyces cerevisiae; chromosome structure and function
Our research focuses on a fundamental question: how does the structure of a eukaryotic chromosome influence gene expression? The primary structural component of the eukaryotic chromosome is the nucleosome, composed of four different histone proteins. Each of these histones can be modified to create nucleosomes with unique characteristics, including the ability to activate or repress gene expression. Therefore, a “histone code” determines accessibility to the genetic code found in the DNA.
Our experiments on gene regulation take advantage of the advanced molecular genetics of budding yeast, a single-celled eukaryote. A powerful combination of classical genetics, molecular biology, and biochemistry can be applied to address the biology of yeast, and these findings are generally applicable to all eukaryotes.
Yeast uses a mechanism known as silencing to regulate expression of genes that dictate the developmental program of the cell. Silencing is achieved by formation of the yeast equivalent of heterochromatin, a repressive chromatin structure. Once established, this gene repression is epigenetically inherited; the expression state becomes a permanent, heritable property of the gene.
Currently, we are focusing on two principle questions:
- Why does establishment of silencing depend on cell cycle progression? We are currently using an inducible system to study the establishment of silencing at yeast telomeres.
- Is silencing influenced by or coordinated with the structural changes in chromosomes that occur as cells progress through DNA replication and mitosis? We are specifically investigating the influence of the cohesin and condensin proteins, involved in chromosome cohesion and compaction.
Recent Publications
Merritt Hickman, Kalyani McCullough, Adrienne Woike, Laura Raducha-Grace, Tania Rozario, Mary Lou Dula, Erica Anderson, Danielle Margalit and Scott Holmes. (2007) Isolation and characterization of conditional alleles of the yeast SIR2 gene. Journal of Molecular Biology 367:1246-1257.
Matecic, M.K., Martins-Taylor, M. Hickman, J. Tanny, D. Moazed, and S. G. Holmes, 2006. New alleles of SIR2 define cell cycle specific silencing functions. Genetics 173: 1939-1950.
Martins-Taylor, K., M.L. Dula, and S.G. Holmes, 2004. Heterochromatin spreading at yeast telomeres occurs in M-phase. Genetics 168: 65-75
Papacs, L.A., Y. Sun, E. Anderson, J. Sun, and S. G. Holmes, 2004. REP3-mediated silencing in Saccharomyces cerevisiae. Genetics 166:79-87
Mirela Matecic, Shelagh Stuart and Scott Holmes, 2002. SIR2-Induced Inviability Is Suppressed by Histone H4 Overexpression. Genetics. 162:973-976.
Holmes, S.G. and M.M. Smith, 2001. Replication of minichromosomes in Saccharomyces cerevisiae is sensitive to histone gene copy number and strain ploidy. Yeast. 18: 291-300.
Dula, M.L. and S.G. Holmes, 2000. Mga2p and Spt23p are modifiers of transcriptional silencing in yeast. Genetics 156: 933-941.
Principal Investigator
Scott Holmes
Graduate Students
Kristen Martins-Taylor
Asmitha Lazarus
Upasana Sharma
Fifth Year Masters Student
Hannah Stubbs
Grant Support: National Science Foundation
