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SMYD2-Mediated Histone Methylation Contributes to HIV-1 Latency.

  • Author(s): Boehm, Daniela
  • Jeng, Mark
  • Camus, Gregory
  • Gramatica, Andrea
  • Schwarzer, Roland
  • Johnson, Jeffrey R
  • Hull, Philip A
  • Montano, Mauricio
  • Sakane, Naoki
  • Pagans, Sara
  • Godin, Robert
  • Deeks, Steven G
  • Krogan, Nevan J
  • Greene, Warner C
  • Ott, Melanie
  • et al.
Abstract

Transcriptional latency of HIV is a last barrier to viral eradication. Chromatin-remodeling complexes and post-translational histone modifications likely play key roles in HIV-1 reactivation, but the underlying mechanisms are incompletely understood. We performed an RNAi-based screen of human lysine methyltransferases and identified the SET and MYND domain-containing protein 2 (SMYD2) as an enzyme that regulates HIV-1 latency. Knockdown of SMYD2 or its pharmacological inhibition reactivated latent HIV-1 in T cell lines and in primary CD4+ T cells. SMYD2 associated with latent HIV-1 promoter chromatin, which was enriched in monomethylated lysine 20 at histone H4 (H4K20me1), a mark lost in cells lacking SMYD2. Further, we find that lethal 3 malignant brain tumor 1 (L3MBTL1), a reader protein with chromatin-compacting properties that recognizes H4K20me1, was recruited to the latent HIV-1 promoter in a SMYD2-dependent manner. We propose that a SMYD2-H4K20me1-L3MBTL1 axis contributes to HIV-1 latency and can be targeted with small-molecule SMYD2 inhibitors.

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