Molecular genetics of gene silencing in yeast 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.

Cell cycle-dependent establishment of transcriptional silencing.

We are using an inducible system to study the establishment of silencing in yeast.  We have found that the onset of silencing is 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 on silencing.

 Sir2 function and metabolism

Sir2 is a histone-modifying enzyme essential for silencing in yeast.  We have discovered that GAPDH, a glycolysis enzyme, interacts with Sir2 and affects transcriptional silencing.  We are determining the mechanism of this regulation and exploring the general effects of metabolism on the efficiency of silencing in yeast.

Inducible silencing at a yeast telomere

Funding: National Science Foundation

Current members: Rebecca Ryznar, Priyanka Moondra, Lisle Winston, Claire Palmer.