Amino acid starvation induces reactivation of silenced transgenes and latent HIV-1 provirus via down-regulation of histone deacetylase 4 (HDAC4)

• DOI: 10.1073/pnas.1202174109
• Publication Date: 2012-07-24T04:48:19Z
• Authors: Ilaria Palmisano; Giulia Della Chiara; Rosa Lucia D’Ambr...; Claudia Huichalaf; Paola Brambilla; Silvia Corbetta; Michela Riba; Rosanna Piccirillo; Sergio Valente; Giorgio Casari; Antonello Mai; Filippo Martinell...; Davide Gabellini; Guido Poli; Maria Vittoria Sc...
• Keywords: HDAC4

The epigenetic silencing of exogenous transcriptional units integrated into the genome represents a critical problem both for long-term gene therapy efficacy and eradication latent viral infections. We report here that limitation essential amino acids, such as methionine cysteine, causes selective up-regulation transgene expression in mammalian cells. Prolonged acid deprivation led to significant reversible increase levels stably transgenes transcribed by means or human promoters HeLa This phenomenon was mediated chromatin modifications, because histone deacetylase (HDAC) inhibitors reproduced starvation-induced up-regulation, transcriptome analysis, ChIP, pharmacological RNAi approaches revealed specific class II HDAC, namely HDAC4, plays role maintaining transgenes. mechanism also operational cells chronically infected with HIV-1, etiological agent AIDS, latency state. Indeed, starvation inhibition HDAC4 promoted reactivation HIV-1 transcription reverse transcriptase activity production + ACH-2 T-lymphocytic but not − U1 promonocytic Thus, leads derepression silenced transgenes, including plasmids retroviruses, process involving inactivation down-regulation HDAC4. These findings suggest targeting might represent unique strategy modulating therapeutic vectors, well proviruses reservoirs without cytotoxicity.