Cell and Developmental Biology Programme Xiang Dong Fu

10/03/202615:00R_473.10_AULACell and Developmental Biology ProgrammeXiang Dong FuWestlake University"The mechanism of Aging"Host: Malhotra, VivekAbstract:The Mechanism of Aging

Xiang-Dong Fu, Westlake University

Aging is characterized by a series of hallmarks, including genome instability, epigenetic alterations, mitochondrial dysfunction, cell senescence, etc. but the cause-and-consequence relationship among these events has remained elusive. A recent report reveals accelerated transcription elongation during aging in diverse organisms from warms to humans. We confirm this by analyzing the time course of nascent RNA production on a common cellular aging model through continuous passage of mesenchymal stem cells (MSCs). On this model, we discover that accelerated transcription leads to extensive transcription readthrough, which in many cases causes transcript fusion via intergenic splicing to generate novel hybrid proteins. Strikingly, knockdown of a specific fusion transcript alleviates aging while overexpression of the fusion transcript enhances aging. Leveraging the new feature of transcription readthrough, we develop a report assay by knocking-in a mCherry expressing circular RNA unit and conduct genome-wide CRISPR screen, revealing a key transcription regulator involved in age-dependent transcription acceleration and readthrough. The CRISPR screen also identifies a large panel of factors functioning in inflammation, DNA replication/repair, and maintenance of genome instability, thus linking literally all hallmarks of aging to the newly elucidated molecular pathway. Collectively, these findings suggest a transcription program that forms a vicious cycle to lead to progressive aging.