Manipulation of the host protein acetylation network by human immunodeficiency virus type 1.

Over the past 15 years, protein acetylation has emerged as a globally important post-translational modification that fine-tunes major cellular processes in many life forms. This dynamic regulatory system is critical both for complex eukaryotic cells and for the viruses that infect them. HIV-1 accesses the host acetylation network by interacting with several key enzymes, thereby promoting infection at multiple steps during the viral life cycle. Inhibitors of host histone deacetylases and bromodomain-containing proteins are now being pursued as therapeutic strategies to enhance current antiretroviral treatment. As more acetylation-targeting compounds are reaching clinical trials, it is time to review the role of reversible protein acetylation in HIV-infected CD4(+) T cells.

Enhancer Connectome Nominates Target Genes of Inherited Risk Variants from Inflammatory Skin Disorders.

The vast majority of polymorphisms for human dermatologic diseases fall in noncoding DNA regions, leading to difficulty interpreting their functional significance. Recent work using chromosome conformation capture technology in combination with chromatin immunoprecipitation (ChIP) has provided a systematic means of linking noncoding variants in active enhancer loci to putative gene targets. Here, we apply H3K27ac HiChIP high-resolution contact maps, generated from primary human T-cell subsets (CD4+ naïve, T helper type 17, and regulatory T cells), to 21 dermatologic conditions associated with single nucleotide polymorphisms from 106 genome-wide association studies. This "enhancer connectome" identified 1,492 HiChIP gene targets from 542 noncoding SNPs (P ≤ 5.0 × 10-8). SNP-containing enhancers from inflammatory skin conditions were significantly enriched at the HLA locus and also targeted several key factors from the JAK-STAT signaling pathway, but nonimmune conditions were not. A focused profiling of systemic lupus erythematosus HiChIP genes identified enhancer interactions with factors important for effector CD4+ T-cell differentiation and function, including IRF8 and members of the Ikaros family of zinc-finger proteins. Our results show the ability of the enhancer connectome to nominate functionally relevant candidates from genome-wide association study-identified variants, representing a powerful tool to guide future studies into the genomic regulatory mechanisms underlying dermatologic diseases.

Metabolic reprogramming of human CD8+ memory T cells through loss of SIRT1.

The expansion of CD8+CD28- T cells, a population of terminally differentiated memory T cells, is one of the most consistent immunological changes in humans during aging. CD8+CD28- T cells are highly cytotoxic, and their frequency is linked to many age-related diseases. As they do not accumulate in mice, many of the molecular mechanisms regulating their fate and function remain unclear. In this paper, we find that human CD8+CD28- T cells, under resting conditions, have an enhanced capacity to use glycolysis, a function linked to decreased expression of the NAD+-dependent protein deacetylase SIRT1. Global gene expression profiling identified the transcription factor FoxO1 as a SIRT1 target involved in transcriptional reprogramming of CD8+CD28- T cells. FoxO1 is proteasomally degraded in SIRT1-deficient CD8+CD28- T cells, and inhibiting its activity in resting CD8+CD28+ T cells enhanced glycolytic capacity and granzyme B production as in CD8+CD28- T cells. These data identify the evolutionarily conserved SIRT1-FoxO1 axis as a regulator of resting CD8+ memory T cell metabolism and activity in humans.

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

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.