Deacetylate to differentiate

Many progenitor cell types start differentiation by turning on transcription. But on page 577, Shen et al. show that oligodendrocytes (OLs)—the myelin-forming cells of the nervous system—require a general transcriptional shutdown for differentiation.The transcriptional slowing is due to histone deacetylation, which compacts chromatin. The authors find that histone H3 must be deacetylated for OL progenitors to start differentiating after they exit the cell cycle. Although this shuts off many genes, typical OL proteins such as myelin were only expressed after global deacetylation, which normally occurred in mice during the first two weeks after birth. This timing might coincide with reduced levels of mitogens, which inhibit deacetylation.

Delaying deacetylation with a drug called VPA similarly delayed OL maturation in mice. VPA is used to treat epilepsy, but the findings suggest that it might be harmful to young children.

In neuronal and astrocyte precursors, the promoters of their fate-inducing transcription factors are inaccessible and must therefore be opened before differentiation. In OL progenitors, in contrast, it is thought that the promoters of genes such as myelin are inactive due to the presence of transcriptional inhibitors. The overall effect of deacetylation is therefore to allow myelin transcription by turning off the expression of these inhibitors.

Deacetylation was followed by histone methylation, which more permanently silences gene expression. By starting with (reversible) deacetylation, OL progenitors probably maintain some plasticity in early stages of differentiation.