Crosstalk between histone modifications indicates that inhibition of arginine methyltransferase CARM1 activity reverses HIV latency

Zhang, Zheng; Nikolai, Bryan C.; Gates, Leah; Jung, Sung Yun; Siwak, Edward B.; He, Bin; Rice, Andrew P.; O’Malley, Bert W.; Feng, Qin

doi:10.1093/nar/gkx550

Cited by 47 publications

(49 citation statements)

References 62 publications

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“…Although we have long understood the positive feedback loop mechanism driven by Tat [38], we lack knowledge of mechanisms that actively silence the provirus. However, recent studies have revealed negative HIV-1 feedback loops that might rely on RNA precursor export [58] or histone modifications through the arginine methyltransferase CARM1 [59]. Interestingly, H3K27ac promotes CARM1-mediated HIV-1 latency.…”

Section: Discussionmentioning

confidence: 99%

Chromatin maturation of the HIV-1 provirus in primary resting CD4+ T cells

Lindqvist

Akusjärvi

Sönnerborg

et al. 2019

Preprint

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25Human immunodeficiency virus type 1 (HIV-1) infection is a chronic condition, where viral 26 DNA integrates into the genome. Latently infected cells form a persistent, heterogeneous 27 reservoir. The reservoir that reinstates an active replication comprises only cells with intact 28 provirus that can be reactivated. 29 We confirmed that latently infected cells from patients exhibited active transcription 30 throughout the provirus. To find transcriptional determinants, we characterized the 31 establishment and maintenance of viral latency during proviral chromatin maturation in 32 cultures of primary CD4 + T-cells for four months after ex vivo HIV-1 infection. As 33 heterochromatin (marked with H3K9me3 or H3K27me3) gradually stabilized, the provirus 34 became less accessible with reduced activation potential. In a subset of infected cells, active 35 marks (i.e., H3K27ac) remained detectable, even after prolonged proviral silencing. After T-36 cell activation, the proviral activation occurred uniquely in cells with H3K27ac-marked 37 proviruses. Our observations suggested that, after transient proviral activation, cells were 38 actively returned to latency. 39 40 Author Summary 41 HIV infection is a devastating disease affecting 35 million people worldwide. Current anti-42 retroviral treatment is highly effective and has made the HIV infection chronic. However, a 43cure is far on the horizon. The problem for an HIV cure is that, even though the virus particles 44 are eradicated, the infected cells maintain the information of remake the virus. This 45 information is integrated in the host cell. The proviral chromatin switches between active and 46 inactive states. Thereby, the infected cells evade both the immune system and death 47 associated with massive viral production. 48Here we have characterized the composition of the proviral chromatin and how it 49 connects with transcription and viral production. In resting primary CD4 + T-cells, we follow 50 the fate of the provirus starting at infection until latency is firmly established. We found that 51 only a fraction of the proviruses switched between the two chromatin states, and thus were 52 able to remain undetectable but still produce new viruses. These proviruses were associated 53 with a specific chromatin mark, allowing us to identify the activatable fraction of infected 54 cells. Our study provides key insights as to detect the remaining HIV-infected cells capable of 55 reseeding the infection and the mechanisms whereby these cells are maintained. 56 57

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Section: Discussionmentioning

confidence: 99%

Chromatin maturation of the HIV-1 provirus in primary resting CD4+ T cells

Lindqvist

Akusjärvi

Sönnerborg

et al. 2019

Preprint

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“…We recently found that H3R26 methylation represses transcription through inhibiting the binding of the Super Elongation Complex (SEC) with H3K27ac, an active transcription mark (Zhang et al, 2017). Thus, the two marks generated by CARM1 can be active or repressive depending on relative levels of each modification.…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Impacts of ER Coactivator Sequential Recruitment

Wang

Feng

et al. 2017

Molecular Cell

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Summary Nuclear receptors recruit multiple coactivators sequentially to activate transcription. This “ordered” recruitment allows different coactivator activities to engage the nuclear receptor complex at different steps of transcription. Estrogen receptor (ER) recruits SRC-3 primary coactivator and secondary coactivators p300/CBP and CARM1. CARM1 recruitment lags behind the binding of SRC-3 and p300 to ER. Combining cryo-EM structure analysis and biochemical approaches, we demonstrate that there is a close crosstalk between early and late recruited coactivators. The sequential recruitment of CARM1 not only adds a protein arginine methyltransferase activity to the ER-coactivator complex but also alters the structural organization of the pre-existing ERE/ERα/SRC-3/p300 complex. It induces a p300 conformational change and significantly increases p300 HAT activity on histone H3K18 residues, which in turn promotes CARM1 methylation activity on H3R17 residues to enhance transcriptional activity. This study reveals a structural role for a coactivator sequential recruitment and biochemical process in ER-mediated transcription.

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“…Moreover, during latency, the HIV-1 promoter is heavily controlled by epigenetic mechanisms, including DNA methylation (Blazkova et al, 2009;Kauder et al, 2009;Chávez et al, 2011) and histone post-translational modifications, such as histone acetylation (Lusic et al, 2003;Jiang et al, 2007;Tyagi and Karn, 2007;Li et al, 2018), methylation (du Chéné et al, 2007Marban et al, 2007;Imai et al, 2010;Friedman et al, 2011;Ding et al, 2013;Tchasovnikarova et al, 2015Tchasovnikarova et al, , 2017Boehm et al, 2017;Nguyen et al, 2017;Zhang et al, 2017;Huang et al, 2019), and crotonylation (Jiang et al, 2018). The degree of DNA methylation on the HIV-1 promoter was long considered controversial due to conflicting observations in patients (Blazkova et al, 2009(Blazkova et al, , 2012Kauder et al, 2009;Ho et al, 2013;Weber et al, 2014).…”

Section: Complexity Of Molecular Mechanisms Regulating Hiv-1 Latencymentioning

confidence: 99%

Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs

Aït-Ammar

Kula

Darcis³

et al. 2020

Front. Microbiol.

128

150

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Quantitative polymerase chain reaction; QVOA, quantitative viral outgrowth assays; Rev, regulator of virion expression; RNA, ribonucleic acid; RNAPII, RNA polymerase II; RT-ddPCR, teverse transcription droplet digital PCR; SAHA, suberoylanilide hydroxamic acid; SIV, simian immunodeficiency virus; SMAC, second mitochondrial activator of caspases; SMYD2, SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domain-containing protein 2; Sp1, specificity protein 1; STAT5, signal transducer and activator of transcription 5; Suv39H1, Suppressor of variegation 3-9 homolog 1

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Crosstalk between histone modifications indicates that inhibition of arginine methyltransferase CARM1 activity reverses HIV latency

Cited by 47 publications

References 62 publications

Chromatin maturation of the HIV-1 provirus in primary resting CD4+ T cells

Chromatin maturation of the HIV-1 provirus in primary resting CD4+ T cells

Structural and Functional Impacts of ER Coactivator Sequential Recruitment

Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs

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