Signals are transmitted to chromatin to facilitate rapid, robust, and selective gene expression within the three billion base-pair genome in response to environmental cues, such as pathogen sensing. The goal of our ongoing research is to reveal mechanisms allowing for this scope and selectivity, and to understand them in the context of dynamic and fluid chromatin and all of its constituents. Our recent studies of pathways that transmit extracellular signals to selectively induce gene expression establish the cooperative function of epigenetic mechanisms (histone modifications) and transcription factor activation and their coordinated regulation by chromatin-associated kinases. We are finding that these signaling-to-chromatin pathways are potent in regulation of enhancer activation and higher order chromatin architecture, both during the inflammatory process and in cancer. In ongoing and future work we extend these studies to understand how epigenetic processes provide an “evolutionary toolbox” for adaptations driven by spatiotemporal changes in gene expression. These studies have potential to synthesize an understanding of the extensive cooption of immune genes for non-immune processes (ex. thermogenesis, neuronal development), reveal novel mechanisms of adaptation, and explain inflammation- and age-associated pathologies.
The capacity of cells to selectively, rapidly, and robustly induce expression of specific genes in response to environmental cues is a requisite feature of complex organisms. Key to this process is what the Josefowicz Lab calls “signaling-to-chromatin” pathways. Of special interest to us is the poorly understood process by which these signals initiate transcription of a small number of select genes with speed and precision in the context of two-meters of “chromatinized” DNA compacted within a complex, micron-scale nuclear environment— a process well described by the metaphor of finding a needle in a haystack, and quickly.
Factors in these signaling-to-chromatin pathways are critical in rapid cellular responses, dysregulated in disease, and frequently co-opted in the process of oncogenesis. However, surprisingly little is known of how activation of kinase cascades transmits information directly to chromatin— composed of histone proteins complexed with DNA— for dynamic regulation of nuclear architecture and chromatin characteristics with consequences for transcription. We are interested in understanding how cells address three primary challenges that exist to accomplish this feat in health and disease:
- Cells must efficiently transmit information from extracellular sensing events via signaling pathways to genes in chromatin.
- These signals, once they reach chromatin in the nuclear environment, must search for and identify the specific genes to be induced by a given stimulus and activate gene promoters and enhancers.
- Even once these select genes are “found”, highly complex transcription machinery must be recruited to these sites and rapidly assembled to drive robust transcription through the body of a gene. These stimulation-induced transcription events frequently occur in contexts where organism survival is at stake—immune responses, neuronal signaling, thermogenesis—and so the speed and scope of these responses is paramount.
- Chromatin-associated kinases, including mitogen and stress-activated protein kinases (MSK), activate signaling transcription factors (NF-kB) and chromatin directly.
- Signaling to chromatin is a critical feature of rapid and robust transcription in response to environmental signals.
- Epigenetic changes associated with chronic inflammation and persistent signaling to chromatin may cause dysregulation of chromatin structure, loss of transcriptional fidelity, and genome instability.
- Incisive study of epigenomic features of chronic inflammation in model organisms and humans has the potential to provide mechanistic insights into inflammation-associated disease (cancer, cardiovascular disease, neurodegenerative disease, etc) and accelerated aging.
- Epigenetic features are likely to be predictive of disease, aging, and responsiveness to therapies, and may themselves represent therapeutic targets.