Certain inducible genes show faster reactivation if they were recently expressed. This epigenetic phenomenon is called transcriptional memory and is inherited for several generations after the first round of induction. During this phase, genes show several conserved molecular features that are essential for faster reactivation: peripheral localization of the gene, binding of poised RNA polymerase II, H2A.Z incorporation, and H3K4me2 modification at the promoter. However, it is unclear how regulatory systems of different genes are modified by transcriptional memory to mount faster reactivation. Furthermore, it is unknown how transcriptional memory evolved and whether it has any adaptive value. To address these questions, I have investigated the mechanism of GAL gene transcriptional memory in yeast. GAL genes show a strong upregulation of expression kinetics during memory that persists for seven cell divisions, making it an excellent model. I found that during memory, GAL genes localize to the nuclear periphery and exhibit the conserved chromatin changes, as seen during transcriptional memory of INO1. However, unlike INO1 memory, peripheral localization is dispensable for faster reactivation of GAL genes. Using both a candidate based approach and a genetic screen, I found that faster reactivation is regulated by factors both upstream and downstream of Gal4 transcription factor and by a domain within Gal4. A Gal1 co-activator, produced during initial induction, acts upstream of Gal4 by neutralizing the Gal80 inhibitor. This leads to the faster uni-modal expression of GAL gene. The faster co-activation by Gal1 is dependent on the interaction of Gal4 central domain with its activation domain. This interaction is necessary for high levels of expression from Gal4. Downstream of Gal4, Tup1 transcription factor together with H2A.Z promote binding of a pre-initiation form of RNA polymerase II at the GAL1 promoter, poising the GAL genes for faster reactivation. The faster expression of GAL gene during memory confers a huge fitness advantage in S. cerevisiae by decreasing the growth lag upon shift to galactose. However, a related yeast species, S. uvarum, does not show similar benefit from memory. Rather, it shows a constitutive memory-like response due to leaky expression of GAL1. The absence of such constitutive memory in S. cerevisiae represents a trade-off for better fitness in mixed sugars. Thus, GAL memory is a recently evolved phenomenon that allows cells to integrate a previous experience (growth in galactose, reflected by Gal1 levels) with current conditions (growth in glucose, potentially through Tup1 function). These inputs modulate both the levels of expression and fraction of cells that expresses GAL genes in a population. The resulting faster expression promotes rapid adaptation to changes in carbon source during memory.

Last modified

• 01/11/2019

Creator

• Varun Sood

DOI

• https://doi.org/10.21985/N27X7N

Subject

• Interdepartmental Biological Sciences (IBiS) Graduate Program

Keyword

• Epigenetic memory
• Adaptive fitness
• Genome organization
• Evolution
• Gene regulation
• GAL genes

Date created

• 2017-01-01

Resource type

• Dissertation

Rights statement

• In Copyright