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Cell Host Microbe. 2017 May 10;21(5):569-579.e6. doi: 10.1016/j.chom.2017.04.011.

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

Author information

1
Gladstone Institute for Virology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
2
Gladstone Institute for Virology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
3
Gladstone Institute for Virology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
4
Gladstone Institute for Virology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA; Pharmaceutical Frontier Research Laboratory, JT, 1-13-2 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
5
AstraZeneca, Waltham, MA 02451, USA.
6
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
7
Gladstone Institute for Virology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: mott@gladstone.ucsf.edu.

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.

KEYWORDS:

H4K20me1; HIV; L3MBTL1; LTR; SMYD2; latency

PMID:
28494238
PMCID:
PMC5490666
DOI:
10.1016/j.chom.2017.04.011
[Indexed for MEDLINE]
Free PMC Article

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