Enhancer Regions Show High Histone H3.3 Turnover That Changes ...

In animal, plant and other eukaryotic cells, DNA wraps around histone proteins to form structures called nucleosomes. This compacts long strands of DNA to fit them inside a cell. However, nucleosomes also act as barriers that can prevent access to the DNA. This affects the activity, or “expression”, of genes because gene expression requires proteins called transcription factors to bind to specific DNA regions. Therefore, nucleosomes must be disrupted or removed in order to access their DNA and allow their genes to be expressed.

Transcription factors can bind to DNA sequences called enhancers to activate nearby genes. Groups of enhancers, called super-enhancers, also exist to further bolster the activity of certain genes, particularly those involved in determining cell identity. Recent work has shown that nucleosomes are frequently lost and then replaced by new ones (in a process referred to as turnover) in DNA regions that include enhancers. Measuring the rate of turnover of nucleosomes can thus provide information about which DNA regions regulate gene expression.

Embryonic stem cells can transform or “differentiate” into any type of cell in the body. During this transformation process, different genes are switched on or off in the cell in order to give it a new identity. It is not known how nucleosome turnover changes when this happens.

Deaton et al. have now developed a new method called time-ChIP that can measure the rate of nucleosome turnover across the entire DNA of a cell. Using this technique to analyze mouse embryonic stem cells revealed that nucleosome turnover occurs rapidly at enhancers. Furthermore, nucleosomes at super-enhancers are particularly dynamic and turn over more quickly than in any other DNA region.

Deaton et al. next analyzed how turnover changes after the mouse embryonic stem cells have developed into neural stem cells. This revealed that the regions of DNA where high turnover occurs change as the cells differentiate, in part because this transformation activates a different set of enhancers. However, the most rapid turnover still takes place at enhancers.

Overall, these observations suggest that the high rate of nucleosome turnover at enhancers makes DNA accessible to transcription factors. The next step is to use the new time-ChIP method to study how nucleosome turnover changes during the processes that pattern gene expression as an animal develops from an embryo.