Regulation of developmentally controlled enhancer activity by extrinsic signals in normal and malignant cells: AP-1 at the center [ChIP-Seq]

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 how extrinsic signals are interpreted and integrated within the genome and lead to systems level responses within a chromatin environment. In this article we touch upon this question by summarizing our work and that of others to explain what is known about signaling responsive cis-regulatory elements and by highlighting the features of AP-1 as one of the most important signaling-responsive transcription factor family. We propose that cytokines and other signals are the main driver of cell differentiation, acting via inducible transcription factors such as AP-1 that transmit signaling processes to the genome and are essential for changing gene expression within a given gene regulatory network. Importantly, inducible transcription factors interact 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.