Gloria A. Brar, Ph.D.

Research

My research aims to unravel the gene regulatory programs that govern meiosis—the specialized cell division and differentiation program that results in the formation of gametes. My lab’s scientific approach is to derive concrete biological insight from large-scale global gene expression datasets while complementing with classical methods. Through such studies in yeast, we have discovered many noncanonical features to meiotic gene regulation, including widespread use of an unconventional mode of gene regulatory control that depends on timed production of noncoding mRNA isoforms, translation initiation at non-AUG codons, translation of thousands of overlooked short genes, and endogenous timed activation of an array of stress-response pathways including the unfolded protein response. Because each of these features reflects an unexpectedly complex type of regulation occurring pervasively in the simplest eukaryote, our findings suggest that there is much that has been missed by existing models for how gene regulation works. By defining the molecular circuitry responsible for this fundamental developmental program, we also aim to illuminate the central principles by which proteins can function and by which the information in genomes is decoded.

As an Innovation Fund investigator, Gloria A. Brar, Ph.D., is teaming with Elçin Ünal, Ph.D., to investigate the stress response pathways in regulating cellular longevity. Gametogenesis, the developmental program that creates reproductive cells, can naturally reset the aging clock, culminating in progeny devoid of pre-existing age-damaged materials. However, the specific critical factors that are eliminated during the rejuvenation process and the mechanism by which this occurs are largely unknown. A similarly intriguing and enigmatic phenomenon in the aging field is hormesis, which involves mild stress-induced stimulation of protective mechanisms leading to beneficial effects including longevity. With spark funding, the Brar and Ünal team will begin to test the hypothesis that gametogenesis is a physiological manifestation of hormesis. The Ünal lab has pioneered robust cellular imaging and molecular genetic tools to study gametogenesis in the context of aging in budding yeast and has uncovered the role of the meiotic Ndt80 transcription factor in driving rejuvenation. The Brar lab has discovered that several stress pathways are transiently and moderately activated during gametogenesis in yeast. Interestingly, a subset of these pathways is activated in response to Ndt80, and thus is a strong candidate for driving cellular rejuvenation. The pair will now combine expertise in molecular genetics, genomics, cell biology, and global gene analysis to further understand the activation of stress pathways during rejuvenation. To determine how stress pathways can control the resetting of age in a cell, they will modulate the activation of key stress pathways in adult yeast cells and identify their downstream targets. This work is central to building a foundation for understanding how cellular quality control pathways influence cell age and could point to new mechanisms for reversing cellular damage to promote longevity.