Large‐scale genetic screens identify BET‐1 as a cytoskeleton regulator promoting actin function and life span

• Published in: Aging cell Vol. 22; no. 1; pp. e13742 - n/a
• Main Authors: Garcia, Gilberto, Bar‐Ziv, Raz, Averbukh, Maxim, Dasgupta, Nirmalya, Dutta, Naibedya, Zhang, Hanlin, Fan, Wudi, Moaddeli, Darius, Tsui, C. Kimberly, Castro Torres, Toni, Alcala, Athena, Moehle, Erica A., Hoang, Sally, Shalem, Ophir, Adams, Peter D., Thorwald, Max A., Higuchi‐Sanabria, Ryo
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-01-2023; John Wiley and Sons Inc
• Subjects: Actin; Actin Cytoskeleton - metabolism; Actins - genetics; Actins - metabolism; Aging; Animals; Autophagy; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Cell division; CRISPR; Cytoskeleton; Cytoskeleton - metabolism; Endocytosis; Exocytosis; Fibroblasts; Genes; Genetic screening; Genomes; Homeostasis; Humans; Lethality; Life span; Longevity - genetics; Nematodes; Ontology; Physiology; Polymerization; Preservation; Proteins; Structure-function relationships; CRISPR; actin; aging
• ISSN: 1474-9718; 1474-9726; 1474-9726
• DOI: 10.1111/acel.13742

The actin cytoskeleton is a three‐dimensional scaffold of proteins that is a regulatory, energyconsuming network with dynamic properties to shape the structure and function of the cell. Proper actin function is required for many cellular pathways, including cell division, autophagy, chaperone function, endocytosis, and exocytosis. Deterioration of these processes manifests during aging and exposure to stress, which is in part due to the breakdown of the actin cytoskeleton. However, the regulatory mechanisms involved in preservation of cytoskeletal form and function are not well‐understood. Here, we performed a multipronged, cross‐organismal screen combining a whole‐genome CRISPR‐Cas9 screen in human fibroblasts with in vivo Caenorhabditis elegans synthetic lethality screening. We identified the bromodomain protein, BET‐1, as a key regulator of actin function and longevity. Overexpression of bet‐1 preserves actin function at late age and promotes life span and healthspan in C. elegans. These beneficial effects are mediated through actin preservation by the transcriptional regulator function of BET‐1. Together, our discovery assigns a key role for BET‐1 in cytoskeletal health, highlighting regulatory cellular networks promoting cytoskeletal homeostasis.
Using a cross‐species screening approach combining genome‐wide CRISPR‐Cas9 screening in human fibroblasts (1) and synthetic lethality screening in Caenorhabditis elegans (2), we identified BET‐1/BRD4 as a novel regulator of the actin cytoskeleton (3). BET‐1/BRD4 promotes actin filament stability in C. elegans and senescent cells, which has direct impact on organismal health, survival, and life span.