TY - JOUR T1 - Transcriptional reprogramming in fused cells is triggered by plasma-membrane diminution JF - bioRxiv DO - 10.1101/832378 SP - 832378 AU - Daniel Feliciano AU - Isabel Espinosa-Medina AU - Aubrey Weigel AU - Kristin M. Milano AU - Zhonghua Tang AU - Tzumin Lee AU - Harvey J. Kliman AU - Seth M. Guller AU - Carolyn M. Ott AU - Jennifer Lippincott-Schwartz Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/11/06/832378.abstract N2 - Developing cells divide and differentiate, and in many tissues, such as bone, muscle, and placenta, cells fuse acquiring specialized functions. While it is known that fused-cells are differentiated, it is unclear what mechanisms trigger the programmatic-change, and whether cell-fusion alone drives differentiation. To address this, we employed a fusogen-mediated cell-fusion system involving undifferentiated cells in tissue culture. RNA-seq analysis revealed cell-fusion initiates a dramatic transcriptional change towards differentiation. Dissecting the mechanisms causing this reprogramming, we observed that after cell-fusion plasma-membrane surface area decreases through increased endocytosis. Consequently, glucose-transporters are internalized, and cytoplasmic-glucose and ATP transiently decrease. This low-energetic state activates AMPK, which inhibits YAP1, causing cell-cycle arrest. Impairing either endocytosis or AMPK prevents YAP1 inhibition and cell-cycle arrest after fusion. Together these data suggest that cell-fusion-induced differentiation does not need to rely on extrinsic-cues; rather the plasma-membrane diminishment forced by the geometric-transformations of cell-fusion cause transient cell-starvation that induces differentiation. ER -