A chromatin twist to silencing choice

Although cells typically transcribe both copies of a particular gene, they sometimes flip off one copy and rely on the other. A histone-modifying protein might help determine which copies are turned on or off by tweaking the structure of chromatin, as Alexander et al. show.

This silencing—called monoallelic expression—reaches an extreme in female mammals, in which one X chromosome almost completely shuts down. Which copy a cell chooses to switch off appears to be random, and the selection mechanism remains unexplained.

Last year, the researchers showed that, in embryonic stem cells, would-be active and inactive X chromosomes differ even before one gets silenced. When the scientists tagged specific genes on the chromosomes using fluorescence in situ hybridization (FISH), one X chromosome typically carried two glowing spots (usually a sign that it will be shut down), whereas its counterpart had one (a sign of future expression). What structural differences between chromosomes this pattern reveals is unknown. Autosomal genes that don't need to be silenced tend to show up as either two single dots or two double dots.

This single dot–double dot (SD) pattern also marked monoallelic genes on autosomes, Alexander et al. found when they examined embryonic stem cells, which haven't yet picked which allele to close down. Before a stem cell made that choice, however, the alleles often flipped between single and double states, indicating that the cell is sometimes undecided about which allele to quiet. Switching also occurred on X chromosomes.

Suspecting that the SD arrangement might reflect a difference in chromatin structure, the researchers tested the effects of deleting the protein Eed, which helps tighten chromatin by methylating histone H3. Loss of Eed reduced the prevalence of SD cells and resulted in more double dot states. A single spot might indicate scrunched together sister chromatids, while a double spot might reveal standoffish sisters. But how Eed chooses which allele to target is unknown. The researchers now want to determine whether the single-spot-on–double-spot-off pattern shown by X chromosomes holds true for autosomes.

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