SMYD2-Mediated Histone Methylation Contributes to HIV-1 Latency

Publication date: 10 May 2017
Source:Cell Host & Microbe, Volume 21, Issue 5
Author(s): Daniela Boehm, Mark Jeng, Gregory Camus, Andrea Gramatica, Roland Schwarzer, Jeffrey R. Johnson, Philip A. Hull, Mauricio Montano, Naoki Sakane, Sara Pagans, Robert Godin, Steven G. Deeks, Nevan J. Krogan, Warner C. Greene, Melanie Ott
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.

Graphical abstract

Teaser

Transcriptional latency of HIV is a last barrier to viral eradication. Boehm et al. identify the lysine methyltransferase SMYD2 as a regulator of HIV-1 latency via histone H4K20me1 methylation at the HIV LTR. Pharmacological SMYD2 inhibitors reactivate latent HIV-1 in primary T cells, suggesting a strategy for therapeutic latency reversal.


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