Silencing of whole regions of chromosomes by packaging them into heterochromatin provides an effective way of shutting off gene expression. But what keeps heterochromatin from invading surrounding regions and turning off genes that need to be expressed? A recent study by Ania Ebert and colleagues provides some important insights into the mechanisms that are involved.

Drosophila melanogaster genetics has provided important tools for probing the details of heterochromatin formation. One of these is the phenomenon of position-effect variegation (PEV), in which expression of a gene is reduced or abolished if it is moved to a region of heterochromatin. Screens for mutations that counteract this effect have identified a class of suppressor of position-effect variegation (Su(var)) genes that include important components of heterochromatin. The product of one of these, Su(var)3-9, methylates the lysine 9 residue of histone H3 (H3-K9), a key step in heterochromatin formation, and it was a screen for suppression of Su(var)3-9-mediated silencing that provided Ebert and colleagues with a clue as to how the spread of silencing is regulated.

The authors screened for mutants that reversed silencing of the white gene that had been translocated to a heterochromatic region, an effect that requires Su(var)3-9 function. The allele that gave the strongest effect — the previously identified Su(var)3-1 — mapped to the JIL-1 gene and caused the opposite phenotype to null mutations in this gene, indicating a gain-of-function effect. JIL-1 encodes a histone kinase, but the Su(var)3-1 mutation had no effect on JIL-1 kinase activity, indicating a second function for this protein.

To pinpoint how JIL-1Su(var)3-1 counteracts silencing, Ebert and colleagues first checked whether this mutation alters patterns of histone methylation, which are crucial for determining the activation state of chromatin. When this turned out not to be the case, the authors proposed that JIL-1Su(var)3-1-mutant proteins might instead affect the expansion of heterochromatic regions along the chromosome.

To test this, they used a PEV rearrangement in which a large chromosomal region that includes the genes Notch and white is moved to a region that lies next to heterochromatin. When two additional copies of Su(var)3-9 are expressed, the region is visibly compacted into a heterochromatic structure, with high levels of H3-K9 dimethylation and expression of Notch and white mutant phenotypes. In a JIL-1Su(var)3-1 background, however, all of these features are reversed, with the translocated region restored to its normal state. Similar results for seven other PEV rearrangements indicate that JIL-1Su(var)3-1 prevents or reverses Su(var)3-9-mediated silencing in a range of situations.

The authors conclude that JIL-1 is a general antagonist of Su(var)3-9 function, although the molecular details have yet to be examined. These results reveal a dynamic process that regulates the balance between silent heterochromatin and active euchromatin, and once again show the importance of Drosophila in epigenetics research.