PT  - JOURNAL ARTICLE
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
TI  - Transcriptional reprogramming in fused cells is triggered by plasma-membrane diminution
AID  - 10.1101/832378
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 832378
4099  - http://biorxiv.org/content/early/2019/11/06/832378.short
4100  - http://biorxiv.org/content/early/2019/11/06/832378.full
AB  - 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.