Spatio-temporal control of nuclear mechanotransduction during EMT

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Abstract

During epithelial-to-mesenchymal transition (EMT), cells undergo profound shape changes and generate mechanical forces. How the nucleus reacts to these mechanical cues, ensuring a tight balance between mechano-protection and mechanotransduction is a key yet unresolved question. Here we show that the transcriptional response to mechanical cues is spatially restricted during EMT. Using Drosophila mesoderm invagination as an integrated model of EMT, we quantified single nuclei deformation, nuclear envelope biophysical properties and transcriptional responses during EMT. We found that two conserved pro-EMT genes, snail (sna) and twist (twi) , respond differently to forces. We show that twi ( but not snail) transcription is enhanced in deformed nuclei, and micromanipulations via optical tweezers is sufficient to rapidly activate twi transcription in vivo . We further reveal the genome wide response to EMT mechanical forces. Surprisingly mechanosensitive genes seem to be polarized along the nuclear apico-basal axis, revealing a mechanoprotective apical nuclear environment. Direct manipulations of the nuclear envelope in living embryos prove sufficient to induce an immediate transcriptional response, but solely when applied to basal nuclear regions. Overall, these results reveal that EMT nuclei respond directly to forces within seconds and in a regionalized manner.

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