Heat shocked human leukemia cells, showing the accumulation of a Polycomb protein (green) in the nucleolus. Image credit: Azkanaz et al. (CC BY 4.0)
All cells in our bodies contain the same sequence of DNA, hence the same genes, in a compartment called the nucleus. Yet different sets of genes are switched on in different types of cells. Cells achieve this by a process called epigenetic regulation. Proteins known as epigenetic regulators modify DNA and its associated proteins in ways that can turn genes on or off. Different types of cells contain different epigenetic regulators, and so express different genes. The Polycomb group proteins (or PcG for short) turn their target genes off and are important to maintain the identity of a cell. When the target genes of PcG proteins are inadvertently switched on, this may lead to changes in the fate of cells, potentially resulting in diseases such as cancer. So, it is important that cells keep the PcG proteins active where necessary, even in the face of stress.
Cellular stresses come in several forms but often interfere with the normal activities of proteins. If cells experience high temperatures, they can experience a stress known as heat shock. This can cause proteins, including PcG proteins, to unfold. Azkanaz et al. have now investigated what happens to PcG proteins in cells experiencing heat shock, and how these cells try to limit the damage this causes.
Azkanaz et al. conducted their experiments on healthy and cancerous human blood cells. After exposing the cells to half an hour of high temperature the PcG proteins disappeared from the genes they were switching off. This means that cells exposed to heat shock lose their epigenetic control machinery, which may lead to permanent changes to epigenetic modifications found across the genome when not quickly reinstalled. PcG proteins, and another group of proteins called the heat shock proteins, were found to move to a compartment within the nucleus called the nucleolus. While the cells had returned to body temperature and were recovering from the heat shock, the heat shock proteins helped the PcG proteins fold back into their proper shapes. The PcG proteins then left the nucleolus and returned to their target genes, where they reinstalled the epigenetic marks.
These experiments show that heat shock causes a temporary loss of epigenetic regulators from their target genes and that the nucleolus acts as a protein quality control center. Future experiments might explore how PcG proteins get to the nucleolus after heat shock and how impaired protein quality control (i.e. upon aging) may lead to alterations of the epigenetic landscape in a cell. Deeper knowledge of this process could help us to understand how cells can recover from stress.
