Large-scale genetic screens identify BET-1 as a cytoskeleton regulator promoting actin health and lifespan
The actin cytoskeleton is a three-dimensional scaffold of proteins that is a regulatory, energy-consuming material with dynamic properties shaping the structure and function of the cell. The proper function of actin is required for many cellular pathways, including cell division, autophagy, chaperone function, endocytosis, and exocytosis (1–5). The breakdown of these cellular processes manifests during aging and exposure to stress, which is in part due to the breakdown of the actin cytoskeleton (5–9). However, the regulatory mechanisms involved in preservation of cytoskeletal form and function are not well understood. Here, we performed a multi-pronged, cross-organismal screen combining a whole-genome CRISPR-Cas9 screen in human fibroblasts with in vivo C. elegans synthetic lethality screening. We identified the bromodomain protein, BET-1, as a key regulator promoting actin health and longevity. Interestingly, overexpression of bet-1 preserves actin health at late age and promotes lifespan and healthspan in C. elegans. These beneficial effects are through preservation of actin,  downstream of the function of BET-1 as a transcriptional regulator. Together, our discovery attributes assigns a key role of BET-1 in cytoskeletal health, highlighting regulatory cellular networks promoting cytoskeletal homeostasis.