Princeton researchers unravel details on how a class of ATP-dependent chromatin remodelers, called ISWI, regulate access to genetic information in a new Nature study.
Researchers reported that ISWI remodelers use a structural feature of the nucleosome, known as the "acidic patch," to remodel chromatin. The nucleosome is the fundamental structural subunit of chromatin, and is often compared to thread wrapped around a spool.
Geoffrey Dann, the study's lead author, says, "The acidic patch is a negatively charged surface, presented on each face of the nucleosome disc, that is formed by amino acids contributed by two different histone proteins, H2A and H2B. Histone proteins are overall very positively charged, which makes the negatively charged acidic patch region of the nucleosome very unique. Recognition of the acidic patch has never before been implicated in chromatin remodeling."
Since ISWI remodelers are known to interact extensively with nucleosomes, the researchers hypothesized that signals, in the form of chemical modifications on histone proteins embedded within nucleosomes, communicate to the remodelers on which nucleosome to act. Using high throughput screening technology, researchers were able to conduct tens of thousands of biochemical measurements to test their assumptions.
The experiments also revealed that remodeling enzymes outside the family of ISWI remodelers also use this structural feature and that it may be a general requirement for chromatin remodeling. In addition, the high throughput screening technology method also generated a vast library of data to drive the design of future studies geared toward further understanding ISWI regulation. With all of these findings, the scientists have hope that they may be able to identify potential cancer therapeutic targets.
Caption: Diagram depicting all histone modifications, mutants, and variants present in the 115-member nucleosome library used in this study. Residues modified or mutated were mapped on to the nucleosome in black. H2A (light yellow), H2B (light red), H3 (light blue), and H4 (light green) modification and mutation locations are indicated by boxes and lines. For clarity, connections are only shown to a single copy of each histone protein. Image courtesy of Nature