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Selective E2F‐dependent gene transcription is controlled by histone deacetylase activity during neuronal apoptosis
Author(s) -
Boutillier AnneLaurence,
Trinh Emmanuelle,
Loeffler JeanPhilippe
Publication year - 2003
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.01581.x
Subject(s) - trichostatin a , histone deacetylase , e2f , histone deacetylase 5 , hdac4 , acetylation , hdac11 , sodium butyrate , histone , histone deacetylase 2 , microbiology and biotechnology , transcription factor , biology , sap30 , chromatin , histone deacetylase inhibitor , histone h4 , gene , genetics
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.