Selective E2F-dependent gene transcription is controlled by histone deacetylase activity during neuronal apoptosis.
The alteration of chromatin through histone acetylation and deacetylation participates in the regulation of gene expression. We have investigated the effects of histone deacetylase inhibition on neuronal fate. We show that treatment of primary neurones with trichostatin A (TSA) or sodium butyrate (NaBu) induces typical features of apoptosis, a cell death that relies on specific genetic programmes. We have further explored the molecular mechanisms implicated in the TSA response and demonstrated that TSA-induced apoptosis is partly dependent on the activation of the transcription factor E2F-1, which has pro-apoptotic functions in these neurones. Furthermore, the increased e2f-1 transcriptional response is probably the result of mechanisms occurring through E2F-responsive elements. Histone acetylation also takes place at the e2f-1 promoter, but this modification is neither required nor by itself sufficient to induce increased transcription at the e2f-1 promoter. Activation might thus occur through acetylation of non-histone proteins binding this regulatory element. Finally, we show that TSA induces the transcription of E2F-dependent genes, such as its cell cycle target cyclin E, but also pro-apoptotic genes, such as Apaf1. Taken together, our results suggest that, in neuroprotective conditions, histone deacetylase activity allows a constitutive repression of the e2f-1 gene in mature neurones in order to ensure survival. Deregulation of this repression will ultimately lead to an E2F-dependent cell death.
Boutillier
Anne-Laurence
AL
Laboratoire de Signalisations Moléculaires et Neurodégénérescence, EA no. 3433, 11 rue Humann, 67085 Strasbourg cedex, France. laurette@neurochem.u-strasbg.fr
Trinh
Emmanuelle
E
Loeffler
Jean-Philippe
JP
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D014157:Transcription Factors; C012589:trichostatin A; D006655:Histone Deacetylases