Apaf-1 is acetylated and open in young neurons (P5) but methylated and silent in mature neurons (P28). Its derepression allows older neurons to apoptose (bottom, left to right) upon release of cyt c (white).

Mature neurons wrap up chromatin around death-sensitizing genes to prevent unwanted apoptosis, say Wright et al.

Neurons die off by the handful during development, when their proliferating brethren can easily replace them. But once neurons mature, they shut off proliferation pathways, and survival becomes precious. One way older neurons become less sensitive to apoptosis is by preventing a protein called Bax from reaching mitochondria, where it pokes holes that let out cytochrome c (cyt c). The new findings identify an additional protective step downstream of cyt c release.

Older sympathetic neurons survived injections of cyt c because they had less Apaf-1, a protein that recruits cyt c to the death-inducing apoptosome complex. Apoptosis, however, still killed mature neurons in response to DNA damage, the authors found. This death resulted from the return of Apaf-1.

In young neurons, Apaf-1 expression is induced by a cell cycle–regulated transcription factor called E2F1. When neurons stop proliferating, E2F1 is shut down along with other cell cycle proteins. DNA damage restored E2F production. But the team found that giving cells E2F1 alone was not enough to force older, undamaged neurons to express Apaf-1. The cells also had to be prodded to open up the chromatin around the Apaf-1 promoter.

In mature neurons, the histones at the Apaf-1 promoter were decorated with methyl groups that signify inaccessible, silent chromatin. The same promoter in young neurons was instead tagged with acetyl groups, which indicate accessibility. When mature neurons were given both E2F1 and drugs that open chromatin by inhibiting histone deacetylases, they again made Apaf-1 and underwent apoptosis in response to cyt c. Since similar drugs are used in chemotherapy, oncologists might want to keep an eye out for neuronal side effects.

It is currently unclear how DNA-damaged neurons initiate pathways that unwrap chromatin around Apaf-1 (and possibly other apoptotic genes). And whether the same thing happens under pathological conditions such as a stroke or neurodegenerative disorders is unknown.


Wright, K.M., et al.
J. Cell Biol.