Comparing Properties of Oscillating Gene Networks in Diverged Species

Abstract

Multiple biological processes occur in a time-dependent fashion. One of the most prevalent ways of regulating rhythmic biology is by controlling the timing and dosage of gene expression. Gene regulatory networks are groups of regulators that control target genes through multiple mechanisms, including direct DNA binding to alter expression dynamics, post-transcriptional activation, and protein degradation. Networks that control oscillating processes, such as circadian rhythms and cell cycles, have several hallmark properties, such as high interconnectedness and the disproportionate presence of certain patterns of regulator-target wiring (network motifs.) They are also self-sustaining and can control large suites of repeating, periodic gene expression.While circadian rhythms and cell cycles are fairly well-studied, there are still some prominent gaps in knowledge. Multiple parasites exhibit remarkably rhythmic life cycles, particularly the Plasmodium genus that causes malaria, but it is unknown whether these rhythms are driven by an oscillator within the parasite or are imposed by pre-existing host rhythms. In addition, the principles which guide oscillator gene regulatory network (oGRN) evolution are only partially understood, and lack examples of network-wide analysis on a finer scale. In this dissertation, I approach both questions primarily by examining the dynamics of periodic gene expression on a whole-transcriptome level. In Chapter 2, I investigate evidence for an innate oscillator in P. falciparum. I found multiple known hallmarks of oGRN-controlled gene expression—independent control of gene expression, conservation of ordering between strains, and genetic control of period length—and conclude that the parasite drives its own asexual reproduction cycle. In Chapter 3, I examine the dynamics of cell cycle-controlled transcription in two closely related species of the budding yeast Saccharomyces cerevisiae, S. paradoxus and S. uvarum. S. cerevisiae is a model organism for cell cycle research, providing a tractable system for studying oGRN evolution principles. I found intriguing differences between the species, including marked changes in the periodicity and gene expression levels of several known members of the core cell cycle oscillation machinery, warranting further study and validation. I conclude by discussing how studying oGRNs of both distantly- and closely-related species to model organisms furthers our understanding of governing evolutionary principles and our ability to form gene network hypotheses.