Graduation Year
2026
Document Type
Master's Thesis
Degree
Master of Science
Program
Biological Science
Partner Organization
Buck Institute for Research on Aging
Program Director
Patti Culross, MD, MPH
First Reader
Pankaj Kapahi, PhD
Second Reader
Sudipta Bar
Abstract
Aging is characterized by a progressive decline in cellular homeostasis, genomic integrity, and regenerative potential, driven in part by the loss of transcriptional regulation over stress response and repair pathways. The Polycomb Repressive Complex 2 (PRC2) maintains transcriptional silencing through histone H3K27 trimethylation after development, and its repressive marks are a hallmark of epigenetic age. The complex’s cofactor, Jarid2, plays a key role in determining target specificity and chromatin recruitment. For this study, we postulated that reducing Jarid2 activity could relieve PRC2-mediated repression, thereby reactivating genes to enhance tissue resilience and delay senescence without inducing full dedifferentiation. To test this, Jarid2 expression was selectively knocked down using a tissue-specific GAL4-UAS RNA interference system in Drosophila melanogaster. Knockdown was performed in ovarian, neural, and photoreceptor tissues, as well as the whole body, to evaluate both local and systemic consequences of PRC2 disruption. This was assessed through lifespan assays, egg counting, and phototaxis response. These health span results were then further confirmed through multi-omics methods to image tissues under knockdown and assess downstream pathway regulation. We found that the loss of Jarid2 reactivated downstream PRC2 targets that are normally silenced by methylation. These transcriptional changes promoted improved tissue maintenance and delayed cellular senescence in aged flies. Chromatin analyses revealed that Jarid2 suppression induced a state of partial reprogramming at the epigenetic level, restoring youthful transcriptional profiles while preserving cellular identity. Together, these findings demonstrate that targeted Jarid2 knockdown reconfigures the PRC2 regulatory landscape to enhance repair and resilience, providing a potential mechanism for delaying age-related functional decline across multiple tissues.