Research Expertise and Interest

meiosis, translation, sORFs, stress responses

Research Description

Regulation of gene expression allows cells to grow, adapt to their environment, and differentiate into new forms. We know the key processes responsible—including transcription, translation, and protein degradation—but have a poor understanding of how they are naturally deployed and integrated to drive cellular change. The Brar lab studies the gene regulatory circuitry that underlies meiotic differentiation, the process that creates gametes. This conserved process involves dramatic and characteristic changes to cell morphology and function that reflect a series of unidirectional transitions in cell state. Meiosis fails frequently, with devastating consequences for fertility and health, but we do not understand the basis of these failures, due in part to gaps in our understanding of normal regulation. My lab has constructed an atlas of gene expression through meiosis, providing a framework to begin to explain its molecular control.

Our studies have also revealed new principles in gene regulation that may broadly apply to natural conditions of cellular change, and that have been missed by model-centric analyses. Canonical models for gene regulation are based on studies of individual genes and rational assumptions, such as a focus on cellular economy. They predate our ability to make genome-scale measurements. Such models tell us, for example, that proteins should be translated from Open Reading Frames (ORFs) that exceed 100 codons and that ORFs should initiate at AUG codons. Cases in which these rules do not fit have largely been treated as exceptions. Our studies of meiosis have shown that both the regions that are expressed and how they are regulated are not well explained by canonical gene regulatory rules. Systems-level studies, complemented with classical approaches, have allowed us to determine that unexpected patterns reflect substantial gaps in our understanding of how gene expression is naturally regulated. We are investigating the basis for these surprising findings, with the goal of discovering new gene regulatory features and explaining how they shape a meiotic cell. Our approach is to use integrated parallel global gene expression measurements and quantitative analytical frameworks, complemented with classical approaches, to gain fresh insight into eukaryotic gene regulatory circuitry.

The rules that govern how cells naturally use their genomic resources over time remain mysterious. Using the approaches described here, we aim to finally define them. We constructed the most comprehensive map of gene expression through a developmental process, including mRNA, translation, and protein measurements for many naturally synchronous stages of meiotic differentiation in budding yeast. We found strong temporal regulation of synthesis and degradation for nearly every gene in the genome, and these patterns were specific enough to enable accurate prediction of gene function. The highly parallel nature of the measurements enabled discovery of gene regulatory strategies that defy canonical models, including the widespread integration of translational and transcriptional control and the synthesis of thousands of non-canonical proteins.