Strongly regulated transcription factors exert an outsized influence in microRNA-regulated networks
Files
(Published version)
Date
2026
Authors
Sourdin, L.
Bracken, J.M.
Gregory, P.A.
Feldker, N.
Brabletz, T.
Brabletz, S.
Khew-Goodall, Y.
Goodall, G.J.
Pillman, K.A.
Bracken, C.P.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Cell Communication and Signaling, 2026; 24(1):63-1-63-21
Statement of Responsibility
Laura Sourdin, Julie M. Bracken, Philip A. Gregory, Nora Feldker, Thomas Brabletz, Simone Brabletz, Yeesim Khew-Goodall, Gregory J. Goodall, Katherine A. Pillman and Cameron P. Bracken
Conference Name
Abstract
Identifying the most biologically meaningful microRNA (miRNA) targets remains challenging, as predictive and biochemical methods yield many weak or non-productive interactions. Transcription factors (TFs) are enriched among miRNA targets and amplify miRNA effects through their broad regulatory influence. Frequently, these same TFs also regulate the miRNA, forming double negative feedback loops that enforce bistable gene expression and cell-fate decisions. We investigated this regulatory motif by focusing on reciprocal repression between the miR-200 family and ZEB1/2, which governs epithelial–mesenchymal plasticity. Employing a system isolating ZEB-dependent effects of miR-200c and combining Weighted Gene Co-expression Network Analysis (WGCNA) with Exon-Intron Split Analysis (EISA), as well as functional cell biology assays, we show this circuit reinforces mutually exclusive epithelial and mesenchymal states through complex networks of intertwined direct and indirect, transcriptional and post-transcriptional, ZEB-dependent and independent mechanisms. Our findings highlight how miRNATF feedback loops can act as bistable switches to lock cell identity and emphasize the pivotal role of strongly regulated TFs within miRNA target networks.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
© The Author(s) 2025. 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/.