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Mechanoresponsive regulation of myogenesis by the force-sensing transcriptional regulator Tono
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International audience. Muscle morphogenesis is a multi-step program, starting with myoblast fusion, followed by myotube-tendon attachment and sarcomere assembly, with subsequent sarcomere maturation, mitochondrial amplification, and specialization. The correct chronological order of these steps requires precise control of the transcriptional regulators and their effectors. How this regulation is achieved during muscle development is not well understood. In a genome-wide RNAi screen in Drosophila, we identified the BTB-zinc-finger protein Tono (CG32121) as a muscle-specific transcriptional regulator. tono mutant flight muscles display severe deficits in mitochondria and sarcomere maturation, resulting in uncontrolled contractile forces causing muscle rupture and degeneration during development. Tono protein is expressed during sarcomere maturation and localizes in distinct condensates in flight muscle nuclei. Interestingly, internal pressure exerted by the maturing sarcomeres deforms the muscle nuclei into elongated shapes and changes the Tono condensates, suggesting that Tono senses the mechanical status of the muscle cells. Indeed, external mechanical pressure on the muscles triggers rapid liquid-liquid phase separation of Tono utilizing its BTB domain. Thus, we propose that Tono senses high mechanical pressure to adapt muscle transcription, specifically at the sarcomere maturation stages. Consistently, tono mutant muscles display specific defects in a transcriptional switch that represses early muscle differentiation genes and boosts late ones. We hypothesize that a similar mechano-responsive regulation mechanism may control the activity of related BTB-zinc-finger proteins that, if mutated, can result in uncontrolled force production in human muscle
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