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. 2020 Feb 24;11(2):147. doi: 10.1038/s41419-020-2340-4

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© The Author(s) 2020

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 6 — a This system recapitulates in a regulatory network all the interactions relevant for the interplay between SETD1B and ZEB1 in the context discussed. The key element of the system is the double positive feedback loop between ZEB1 and SETD1B (ZEB1 → SETD1B → ZEB1/H3K4me3 → ZEB1). Through this loop each protein can reinforce the activity/expression of the other. This can amplify the activation of the circuit. b Under low transient stimulation (S) of ZEB1, the circuit responds with transient, low level activation even in the absence of p21. c The structure of the circuit suggests a medium but transient stimulation (S) of ZEB1. This activation can provoke an irreversible enhancement in the expression and activity of both molecules via triggering of SETD1B and feedback-regulating ZEB1 activation. This in turn may trigger the EMT phenotype by consistent, long-lasting inhibition of epithelial marker E-Cadherin. In solid red lines, we represent the long-lasting activation of the circuit, while the black dashed lines represent the transient activation of the circuit that would appear in case of disruption of the positive feedback loop.