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HYPOTHESIS AND THEORY article
Front. Epigenet. Epigenom.
Sec. Chromatin Epigenomics
Volume 2 - 2024 |
doi: 10.3389/freae.2024.1465958
This article is part of the Research Topic Epigenetics and genomic causality in development and chromatin research View all 3 articles
Regulation of developmentally controlled enhancer activity by extrinsic signals in normal and malignant cells: AP-1 at the centre
Provisionally accepted- 1 Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia
- 2 University of Birmingham, Birmingham, United Kingdom
The ability of cells to respond to external stimuli is one of the characteristics of life as we know it. Multicellular organisms have developed a huge machinery that interprets the cellular environment and instigates an appropriate cellular response by changing gene expression, metabolism, proliferation state and motility. Decades of research have studied the pathways transmitting the various signals within the cell. However, whilst we know most of the players, we know surprisingly little about the mechanistic details of how extrinsic signals are interpreted and integrated within the genome. In this article we revisit the long-standing debate of whether factors regulating cellular growth (cytokines) act in an instructive or permissive fashion on cell fate decisions. We touch upon this topic by highlighting the paradigm of AP-1 as one of the most important signaling-responsive transcription factor family and summarize our work and that of others to explain what is known about cytokine responsive cis-regulatory elements driving differential gene expression. We propose that cytokines and, by extension, multiple types of external signals are the main drivers of cell differentiation and act via inducible transcription factors that transmit signaling processes to the genome and are essential for changing gene expression to drive transitions between gene regulatory networks. Importantly, inducible transcription factors cooperate with cell type specific factors within a pre-existing chromatin landscape and integrate multiple signaling pathways at specific enhancer elements, to both maintain and alter cellular identities. We also propose that signaling processes and signaling responsive transcription factors are at the heart of tumor development.
Keywords: Signaling Pathways, development, Activator-Protein-1 (AP-1) family of transcription factors, Hematopoiesis, enhancers, Chromatin Priming, VEGF-signaling, Runx1
Received: 17 Jul 2024; Accepted: 03 Sep 2024.
Copyright: © 2024 Maytum, Obier, Cauchy and Bonifer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Constanze Bonifer, University of Birmingham, Birmingham, United Kingdom
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