Title

Transcriptomic Analysis of the Gcr1 Regulatory Network and a Yeast Model for Leukemogenesis

Date of Award

2006

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Sciences

First Advisor

George M. Santangelo

Advisor Department

Biological Sciences

Abstract

In all organisms, the ability to alter cellular metabolism through rapid changes in gene expression is crucial to the proliferative response to nutrients. In Saccharomyces cerevisiae, this transcriptomic reprogramming requires Gcr1, a regulator of glycolytic, ribosomal protein, and cyclin genes. I report here the comprehensive genome-wide expression profiling of gcr1 Δ cells, including both a steady state analysis and the immediate response to glucose. Despite the similar transcriptional profiles and growth phenotype of gcr1 Δ cells in all carbon sources tested, I observe the large cell phenotype only in the presence of repressing sugars; this coincides with defective polyribosome levels. Interestingly, deletion of GCR1 also results in aberrant derepression of a wide variety of glucose-repressed loci; I show that glucose-grown ger1 Δ cells actively respire, demonstrating that this global alteration in gene expression corresponds to significant changes at the physiological level. The data therefore provide an integrated view of the transcriptomic, phenotypic and metabolic consequences of GCR1 deletion and support the classification of Gcr1 as a global transcriptional regulator. I further identify a physical and functional link between Gcr1 and the SAGA component Sgf73 and characterize the predominance of coiled-coil interaction domains in these and other transcriptional regulatory proteins. By using PSI-BLAST analysis, I identify the first known homologs of Gcr1 in higher eukaryotes including Rpb1, the essential large subunit of Pol II, and MLL3, a common target of leukemogenic chromosomal translocations that result in acute myeloid and lymphoid leukemias. Functional similarities between the Gcr1 activation mechanism and the leukemogenic mode of MLL activation allow me to propose a yeast model for studying the transcriptional aberrations characteristic of acute human leukemias.