Heterochromatin is a key player in gene regulation. This tightly packed complex of nuclear proteins and DNA is usually found in regions where genes are silenced. Unfortunately, how it works is not fully understood.
Now, researchers from the Lawrence Berkeley National Laboratory have shown that heterochromatin organizes DNA into different physical compartments inside a cell nucleus to promote distinct genome functions. And it does this using liquid-liquid phase separation, the same mechanism that separates mixtures of oil and water, as recently reported in Nature.
Previously, scientists thought that heterochromatin’s dense packing silenced genes by preventing regulatory proteins from gaining access. The theory was that the tightly wound strands made it difficult for the proteins to get to the genetic material inside. However, this didn’t explain why heterochromatin excludes some small proteins while admitting other large ones.
The new study, using fruit flies and mouse cells, identified a different mechanism. The Berkeley Lab researchers observed two non-mixing liquids in the cell nucleus: one that contained silenced heterochromatin and another that contained DNA with expressed genes. They found that the heterochromatin droplets fused together like drops of oil in water, indicating that the distinct heterochromatin compartments arise through liquid-liquid phase separation.
“We are excited about these findings because they explain a mystery that’s existed in the field for a decade,” said lead author Amy Strom, a biology graduate student at the University of California, Berkeley, in a recent news release. “That is, if compaction controls access to silenced sequences, how are other large proteins still able to get in? Chromatin organization by phase separation means that proteins are targeted to one liquid or the other based not on size, but on other physical traits, like charge, flexibility, and interaction partners.”
The researchers hope a better understanding of how heterochromatin works will ultimately lead to improved gene therapy or other treatments that rely on accurate regulation of gene expression.