The Many Faces of Gene Regulation: Extrinsic Control of Cell Fate and Function

Abstract

Cell fate and function is determined by the complex interplay between extrinsic and intrinsic factors. Environmental signals play important roles in the processes that underlie cell behavior. All cells have the ability to recognize extracellular molecules and can respond by altering the transcriptional programs that establish and maintain cell identity. While extrinsic stresses are known to affect gene regulation, exactly how these signals are integrated into highly specific transcriptional programs to drive certain cell fates remains poorly understood. The objective of the research presented here was to dissect the mechanisms through which environmental signals regulate gene expression and control cell fate. Our work revealed that activation of intracellular signaling pathways by environmental molecules is directly received, interpreted, and answered to, by chromatin. This leads to transcriptional activation or repression. The chromatin landscape is highly dynamic and exceedingly reactive to external stress. We identified several mechanisms by which chromatin adapts to extrinsic signals and modifies gene expression. Environmental conditions can be sensed by multifunctional proteins that masquerade as transcription factors (TFs) or transcriptional co-activators and convert the stress into a transcriptional response. We observed that nucleotide deficiency is interpreted by the RNA binding protein DDX21 that also functions as a chromatin factor to facilitate transcription elongation. Following stress sensing, DDX21 disengages from chromatin to enforce transcriptional pausing during suboptimal cellular conditions. Instead, DDX21 engages mRNAs to potentially stabilize transcripts that are required to restore homeostasis. A stress-related function for chromatin factors and RNA binding proteins could allow for the regulation of various cellular processes at once. We propose that the mechanism of chromatin factors functioning as stress sensors is evolutionarily conserved and suggest that other chromatin proteins with similar dual functions likely exist. This research also found that the chromatin structure itself facilitates induction of stress response genes. The local nucleosome structure determines the responsiveness of individual regulatory elements to stress. We found that stress-inducible enhancers are pre-marked with histone variant H2A.Z-containing nucleosomes. These enhancer nucleosomes are not prohibitive of TF binding. Rather, the observed epigenetic characteristics enable rapid chromatin remodeling and quick, transient alterations in gene expression. The stimuli-responsive enhancer landscape is such that it can promptly receive, and respond to, signals from the extracellular environment. We hypothesize that the chromatin architecture of stimuli-responsive regulatory regions is organized at earlier stages of cell lineage specification. Precisely when and how the epigenetic pre-marking of inducible enhancers happens is currently unknown and requires further investigation. Together, the work described here identified how extrinsic signals directly impact chromatin. Adaptive mechanisms such as multifunctional chromatin factors, epigenetic pre-marking of regulatory regions, and swift chromatin remodeling permit acute regulation of genes specific to cell fate. While our work specifically focused on transcriptional control of cells from the two most regenerative systems of the body, those being the skin and the blood, our findings may hold true for other cell types.