ZEB1 insufficiency causes corneal endothelial cell state transition and altered cellular processing

Frausto, R. F.; Chung, D. D.; Boere, P. M.; Swamy, V. S.; Duong, H. N. V.; Kao, L.; Azimov, R.; Zhang, W.; Carrigan, L.; Wong, D.; Morselli, M.; Zakharevich, M.; Hanser, E. M.; Kassels, A. C.; Kurtz, I.; Pellegrini, M. F.; Aldave, A. J.

doi:10.1101/547927

bioRxiv · 10.1101/547927

ZEB1 insufficiency causes corneal endothelial cell state transition and altered cellular processing

Frausto, R. F.·Chung, D. D.·Boere, P. M.·Swamy, V. S.·Duong, H. N. V.·Kao, L.·Azimov, R.·Zhang, W.·Carrigan, L.·Wong, D.·Morselli, M.·Zakharevich, M.·Hanser, E. M.·Kassels, A. C.·Kurtz, I.·Pellegrini, M. F.·Aldave, A. J.

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Abstract

The zinc finger e-box binding homeobox 1 (ZEB1) transcription factor is a master regulator of the epithelial to mesenchymal transition (EMT), and of the reverse mesenchymal to epithelial transition (MET) processes. ZEB1 plays an integral role in mediating cell state transitions during cell lineage specification, wound healing and disease. EMT/MET are characterized by distinct changes in molecular and cellular phenotype that are generally context-independent. Posterior polymorphous corneal dystrophy (PPCD), associated with ZEB1 insufficiency, provides a new biological context in which to understand and evaluate the classic EMT/MET paradigm. PPCD is characterized by a cadherin-switch and transition to an epithelial-like transcriptomic and cellular phenotype, which we study in a cell-based model of PPCD generated using CRISPR-Cas9-mediated ZEB1 knockout in corneal endothelial cells (CEnCs). Transcriptomic and functional studies support the hypothesis that CEnC undergo a MET-like transition in PPCD, termed endothelial to epithelial transition (EnET), and lead to the conclusion that EnET may be considered a corollary to the classic EMT/MET paradigm.

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Frausto, R. F., Chung, D. D., Boere, P. M., Swamy, V. S., Duong, H. N. V., Kao, L., Azimov, R., Zhang, W., Carrigan, L., Wong, D., Morselli, M., Zakharevich, M., Hanser, E. M., Kassels, A. C., Kurtz, I., Pellegrini, M. F., Aldave, A. J.. 2019-02-12. ZEB1 insufficiency causes corneal endothelial cell state transition and altered cellular processing. https://doi.org/10.1101/547927

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