UC Berkeley

The endoplasmic reticulum (ER) is a membrane-bound organelle that carries out a range of essential cellular functions, from protein trafficking to lipid homeostasis to inter-organelle signaling. These functions rely on the maintenance of an intricate membrane architecture that is rapidly remodeled in response to changes in cellular demand, such as the presence of external stressors or the onset of cell differentiation. Work in the last fifteen years has greatly expanded our knowledge of how ER membranes are shaped in unperturbed cells, but mechanisms controlling dynamic ER remodeling under changing conditions, especially during cell differentiation, are not well understood. Here, we use budding yeast meiosis as a model system to study gene regulation and ER remodeling in a developmental context.

In chapter 2, we identify a series of developmentally regulated changes in ER morphology and composition that simultaneously control organelle inheritance and degradation. During meiosis, the cortical ER undergoes reticulon-dependent fragmentation before dramatically collapsing away from the plasma membrane (PM). While the vast majority of ER collapses during this process, a subset of ER fragments is retained at the cell cortex via ER-PM tethering proteins and thereby excluded from gametes. Cortically retained ER is degraded late in spore packaging, while collapsed ER is subject to selective autophagy, indicating that multiple parallel pathways exist to eliminate unwanted ER during meiosis. These findings raise new questions about the role of ER remodeling events in developmental quality control, which we discuss in chapter 3.

In chapter 4, we leverage a genomics approach to address a fundamental question in gene regulation: why does mRNA expression often fail to predict protein abundance? Using global parallel measurements of mRNA abundance, translation, and protein levels over the course of meiosis, we identify genes with poor mRNA:protein correlation over time. We show that hundreds of these genes are regulated by transcript isoform toggling, in which a poorly translated extended transcript isoform prevents expression of an efficiently translated canonical isoform. Thus, apparent transcriptional upregulation can lead to protein downregulation in an isoform-dependent manner, with important implications for the interpretation of genomics datasets.