How cells stress-out differently
February 22, 2018
The heart pumps faster, the breath quickens, and the blood pressure rises. These are all signs of acute stress. In response to stress, a cocktail of stress hormones is released into the blood stream, which transports the hormones to the multiple tissues and cell types of our body. Consequently, the entire body is exposed to stress hormones. However, although all cells are affected by the same stimulus, they respond with a wide spectrum of different physiological reactions. In fat cells, for example, energy reserves are mobilized, whereas an immune-suppressive response is observed in the cells of the immune system. This raises the question, how cells can respond differently to stress despite the fact that all cells of an organism share the same genome.
This is one of the fundamental questions addressed by the group of Sebastiaan Meijsing at the Max Planck Institute for Molecular Genetics (MPIMG) in Berlin. Many of the distinct physiological responses to stress are a consequence of cell-type specific changes in gene expression. For example, cells respond by increasing or decreasing the number of RNA transcripts, this is the part of the DNA that is transcribed, in response to stress. To further investigate how cells respond to stress signals, the researchers of the Meijsing group used genome editing to delete enhancers from the genome of cells derived from lung and studied how the altered cells responded to stress. This enabled the identification of enhancers that facilitate stress-induced changes in gene expression in this specific cell type. Next, the activity of these enhancers was tested in a cell type of different origin: bone cells. To their surprise, one specific enhancer they tested contributed to the stress-induced regulation of other gene transcripts in bone cells than in lung cells. In cells derived from bone, a DNA segment directly flanking the enhancer was activated in response to stress whereas in cells derived from lung a different transcript located at a great distance from the enhancer was switched on.
“Imagine you have only one outlet to run either your toaster or your water heater”, Meijsing explains. "In principle both would work, but with only one outlet you have to choose which devise to plug in”. This is similar to what happens in these two cell types. The studied enhancer is able to activate either the nearby or the distal DNA segment.” But how does the enhancer decide which of the two genome segments has to be activated in which cell? As cells differentiate and commit to a specific cell fate, differences in how the genome is folded can allow or restrict interactions between enhancers and genes. “For the studied region, there is evidence that the way the genome is folded in bone cells allows it to interact with the nearby gene, whereas in the lung cells, a distinct genome architecture guides the activity of the enhancer towards the distal DNA segment”, Meijsing says. “Such "reusing" of existing enhancers towards different transcripts allows the organism to produce distinct products in respond to stress. This may contribute to the diversity in physiological responses to stress by repurposing active enhancers to distinct genes in different cell types.”