SMYD2-Mediated Histone Methylation Contributes to HIV-1 Latency

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

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.

MeSH terms

  • CD4-Positive T-Lymphocytes
  • Cell Line
  • Chromatin / chemistry
  • Chromatin / genetics
  • Chromosomal Proteins, Non-Histone / metabolism
  • DNA, Recombinant
  • Female
  • HEK293 Cells
  • HIV-1 / genetics
  • HIV-1 / physiology*
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histones / chemistry
  • Histones / metabolism*
  • Humans
  • Lysine / metabolism
  • Methylation
  • Promoter Regions, Genetic
  • RNA, Small Interfering
  • Repressor Proteins
  • T-Lymphocytes / virology
  • Tumor Suppressor Proteins
  • Virus Latency / physiology*

Substances

  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • DNA, Recombinant
  • Histones
  • L3MBTL1 protein, human
  • RNA, Small Interfering
  • Repressor Proteins
  • Tumor Suppressor Proteins
  • Histone-Lysine N-Methyltransferase
  • SMYD2 protein, human
  • Lysine