Chromatin modification of Apaf-1 restricts the apoptotic pathway in mature neurons

Although apoptosis has been extensively studied in developing neurons, the dynamic changes in this pathway after neuronal maturation remain largely unexplored. We show that as neurons mature, cytochrome c- mediated apoptosis progresses from inhibitor of apoptosis protein-dependent to -independent regulation because of a complete loss of Apaf-1 expression. However, after DNA damage, mature neurons resynthesize Apaf-1 through the cell cycle-related E2F1 pathway and restore their apoptotic potential. Surprisingly, we find that E2F1 is sufficient to induce Apaf-1 expression in developing but not mature neurons. Rather, Apaf-1 up-regulation in mature neurons requires both chromatin derepression and E2F1 transcriptional activity. This differential capacity of E2F1 to induce Apaf-1 transcription is because of the association of the Apaf-1 promoter with active chromatin in developing neurons and repressed chromatin in mature neurons. These data specifically illustrate how the apoptotic pathway in mature neurons becomes increasingly restricted by a novel mechanism involving the regulation of chromatin structure.