bioRxiv preprint doi: https://doi.org/10.1101/2021.08.26.457621; this version posted August 27, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. KLF4 induces Mesenchymal - Epithelial Transition (MET) by suppressing multiple EMT-inducing transcription factors Running title: KLF4 induces mesenchymal-epithelial transition (MET) Ayalur Raghu Subbalakshmi1, Sarthak Sahoo1, Isabelle McMullen2, Aaditya Narayan Saxena3, Sudhanva Kalasapura Venugopal, Jason Somarelli2,4*, Mohit Kumar Jolly1* 1 Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, India 2 Department of Medicine, Duke University, Durham, NC, United States 3 Department of Biotechnology, Indian Institute of Technology, Kharagpur, India 4 Duke Cancer Institute, Duke University, Durham, NC, United States Authors to whom correspondence to be addressed:
[email protected] (J.A.S),
[email protected] (M.K.J.) Abstract Epithelial-Mesenchymal Plasticity (EMP) refers to reversible dynamic processes where cells can transition from epithelial to mesenchymal (EMT) or from mesenchymal to epithelial (MET) phenotypes. Both these processes are modulated by multiple transcription factors acting in concert. While EMT-inducing transcription factors (TFs) – TWIST1/2, ZEB1/2, SNAIL1/2/3, GSC, FOXC2 – are well-characterized, the MET-inducing TFs are relatively poorly understood (OVOL1/2, GRHL1/2). Here, using mechanism-based mathematical modeling, we show that the transcription factor KLF4 can delay the onset of EMT by suppressing multiple EMT-TFs. Our simulations suggest that KLF4 overexpression can promote phenotypic shift toward a more epithelial state, an observation suggested by negative correlation of KLF4 with EMT-TFs and with transcriptomic based EMT scoring metrics in cancer cell lines.