Signal to reshape

In eukaryotes, ATP-dependent chromatin-remodelling complexes have an important function in regulating promoter accessibility for transcription. Complexes such as SWI2–SNF2 alter — or 'remodel' — the nucleosome architecture using energy from ATP hydrolysis. Little is known about how chromatin-remodelling activity is regulated. However, two reports in Science Express now reveal a link between the small-molecule inositol polyphosphates and chromatin remodelling.

In a genetic screen for mutants defective in transcription of the phosphate-responsive PHO5 gene, Erin O'Shea and colleagues identified mutations in ARG82/IPK2 — a gene encoding a nuclear inositol polyphosphate kinase. The importance of this kinase in PHO5 induction was confirmed, as the PHO5 messenger RNA level and chromatin-remodelling activity were reduced in an arg82/ipk2 mutant strain.

O'Shea and colleagues then showed, by assaying PHO5 induction in various strains each containing a different defective chromatin-remodelling component, that the SWI–SNF and INO80 complexes, but not others, are required for efficient remodelling of PHO5 chromatin. Next, they examined the effects of various mutant enzymes of the inositol polyphosphate pathway on PHO5 transcription. O'Shea and co-workers found that the transcriptional defect is due to the lack of inositol tetrakisphosphate (InsP₄) and inositol pentakisphosphate (InsP₅) — rather than the accumulation of inositol triphosphate (InsP₃), or the lack of inositol hexakisphosphate (InsP₆), the final product in the synthesis pathway.

So, what is the connection between inositol polyphosphate metabolism and chromatin remodelling? A preliminary insight was obtained by carrying out chromatin immunoprecipitation experiments. Deletion of ARG82/IPK2 decreased the recruitment of INO80 to the phosphate-responsive promoters of PHO5 and PHO84 , and SNF2 to PHO84, which implies that InsP₄/InsP₅ metabolism regulates the function of chromatin-remodelling complexes.

Using an in vitro approach, Carl Wu and colleagues tested the effects of various inositol polyphosphates on several chromatin-remodelling complexes in a nucleosome mobilization assay. Nucleosome mobilization — as well as ATPase activity — by the NURF, ISW2, and INO80 complexes was inhibited by InsP₆. By contrast, InsP₆ had no effect on SWI–SNF, but InsP₄ and InsP₅ stimulated nucleosome mobilization and ATP hydrolysis of SWI–SNF — which is consistent with O'Shea's data.

Through in vivo studies, Wu and co-workers showed that the mRNA level of the inositol-1-phosphate synthase ( INO1 ) gene was reduced in an arg82/ipk2 mutant strain and could be rescued by introduction of wild-type IPK2, which, again, confirms that InsP₄ and InsP₅ products are indeed required for gene expression.

So, inositol polyphosphates can modulate chromatin-remodelling activity of various complexes including INO80, SNF2 and ISW2. Yet the mechanisms by which inositol polyphosphates affect the recruitment of chromatin-remodelling complexes are still unclear. Future studies of inositol polyphosphate metabolism and its regulation by different physiological conditions might further uncover this signalling link to chromatin.