Bromodomain and Extra-terminal (BET) Bromodomain Inhibition Activate Transcription via Transient Release of Positive Transcription Elongation Factor b (P-TEFb) from 7SK Small Nuclear Ribonucleoprotein

Bartholomeeusen, Koen; Xiang, Yang; Fujinaga, Koh; Peterlin, B. Matija

doi:10.1074/jbc.m112.410746

Cited by 181 publications

(177 citation statements)

References 39 publications

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“…Among them, BET inhibitors have been suggested to have latency-reversing effects in some model systems, although they do not appear to allow the recovery of latent provirus from resting CD4 ϩ T cells of aviremic patients as efficiently as HDACis (52)(53)(54). However, it is remarkable that demethylation of the HIV LTR sensitized the proviral promoter to the effects of JQ1 (Fig.…”

Section: Discussionmentioning

confidence: 99%

H3K27 Demethylation at the Proviral Promoter Sensitizes Latent HIV to the Effects of Vorinostat in Ex Vivo Cultures of Resting CD4 ⁺ T Cells

Tripathy

McManamy

Burch

et al. 2015

J Virol

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Histone methyltransferase inhibitors (HMTis) and histone deacetylase inhibitors (HDACis) are reported to synergistically induce the expression of latent human immunodeficiency virus type 1 (HIV-1), but studies have largely been performed with cell lines. As specific and potent HMTis directed at EZH1 (enhancer of zeste 2 Polycomb repressive complex 2 subunit 1)/EZH2 are now in human testing, we wished to rigorously test such an inhibitor in a primary resting T-cell model of HIV latency. We found that GSK343, a potent and selective EZH2/EZH1 inhibitor, reduced trimethylation of histone 3 at lysine 27 (H3K27) of the HIV provirus in resting cells. Remarkably, this epigenetic change was not associated with increased proviral expression in latently infected resting cells. However, following the reduction in H3K27 at the HIV long terminal repeat (LTR), subsequent exposure to the HDACi suberoylanilide hydroxamic acid or vorinostat (VOR) resulted in increases in HIV gag RNA and HIV p24 antigen production that were up to 2.5-fold greater than those induced by VOR alone. Therefore, in primary resting CD4 ؉ T cells, true mechanistic synergy in the reversal of HIV latency may be achieved by the combination of HMTis and HDACis. Although other cellular effects of EZH2 inhibition may contribute to the sensitization of the HIV LTR to subsequent exposure to VOR, and to increase viral antigen production, this synergistic effect is directly associated with H3K27 demethylation at nucleosome 1 (Nuc-1). Based upon our findings, the combination of HMTis and HDACis should be considered for testing in animal models or clinical trials. IMPORTANCEDemethylation of H3K27 mediated by the histone methyltransferase inhibitor GSK343 in primary resting T cells is slow, occurring over 96 h, but by itself does not result in a significant upregulation of cell-associated HIV RNA expression or viral antigen production. However, following H3K27 demethylation, latent viral expression within infected primary resting CD4 ؉ T cells is synergistically increased upon exposure to the histone deacetylase inhibitor vorinostat. Demethylation at H3K27 sensitizes the HIV promoter to the effects of an HDACi and provides a proof-of-concept for the testing of combination epigenetic approaches to disrupt latent HIV infection, a necessary step toward the eradication of HIV infection. C urrent antiretroviral therapy (ART) potently suppresses human immunodeficiency virus type 1 (HIV-1) replication; however, HIV infection persists (1, 2). The primary reservoir of persistent infection is a small pool of latently infected resting central memory CD4 ϩ T cells (3-5). This reservoir must be targeted in any attempt to eradicate HIV-1 infection. Latent HIV infection is defined as dormant, nonreplicating virus that can be recovered following activation of the latently infected cell. However, a recent study found that a single exposure to latency-reversing agents, even a broad mitogenic signal, does not reverse latency universally throughout a population of infected cells,...

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Section: Discussionmentioning

confidence: 99%

H3K27 Demethylation at the Proviral Promoter Sensitizes Latent HIV to the Effects of Vorinostat in Ex Vivo Cultures of Resting CD4 ⁺ T Cells

Tripathy

McManamy

Burch

et al. 2015

J Virol

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“…Immunoprecipitations were performed as described before (37). HEK293 or HEK293T cells (ϳ5 ϫ 10 6 ) were lysed on ice (10 min) in lysis buffer (20 mM HEPES, pH 7.4, 150 mM NaCl, 0.1% NP-40, 0.5% Triton X-100).…”

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confidence: 99%

Cyclin-Dependent Kinase 12 Increases 3′ End Processing of Growth Factor-Induced c-FOS Transcripts

Eifler

Shao

Bartholomeeusen

et al. 2015

Molecular and Cellular Biology

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Transcriptional cyclin-dependent kinases (CDKs) regulate RNA polymerase II initiation and elongation as well as cotranscriptional mRNA processing. In this report, we describe an important role for CDK12 in the epidermal growth factor (EGF)-induced c-FOS proto-oncogene expression in mammalian cells. This kinase was found in the exon junction complexes (EJC) together with SR proteins and was thus recruited to RNA polymerase II. In cells depleted of CDK12 or eukaryotic translation initiation factor 4A3 (eIF4A3) from the EJC, EGF induced fewer c-FOS transcripts. In these cells, phosphorylation of serines at position 2 in the C-terminal domain (CTD) of RNA polymerase II, as well as levels of cleavage-stimulating factor 64 (Cstf64) and 73-kDa subunit of cleavage and polyadenylation specificity factor (CPSF73), was reduced at the c-FOS gene. These effects impaired 3′ end processing of c-FOS transcripts. Mutant CDK12 proteins lacking their Arg-Ser-rich (RS) domain or just the RS domain alone acted as dominant negative proteins. Thus, CDK12 plays an important role in cotranscriptional processing of c-FOS transcripts.

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“…Besides the inhibition of Brd4-chromatin interaction, JQ1 also leads to a transient release of P-TEFb from the 7SK snRNP. The released P-TEFb was found to associate with Brd4 and the SEC, which also contributes to HIV-1 transcription and latency activation (Bartholomeeusen et al, 2012;Li et al, 2013).…”

Section: Brd4-p-tefb Interaction and Its Effect On Hiv-1 Transcriptiomentioning

confidence: 99%

“…However, JQ1 has been shown to cooperate well with other well-known latency activators such as SAHA and HMBA (Bartholomeeusen et al, 2012), which may potentially prime the system to allow JQ1 to function properly. Finally, since JQ1 has been developed as an anti-cancer and growth-suppressive agent due to its inhibition of Brd4-dependent recruitment of P-TEFb to many primary response genes such as c-myc (Delmore et al, 2011;Bartholomeeusen et al, 2012), its Tat-specific effect in activating HIV-1 latency ensures that it does not induce general T cell activation, an unwanted side effect of latency reactivation. Indeed, the changes in global gene expression induced by JQ1 or αCD3/αCD28 have been compared through a microarray analysis, which indicates that JQ1 down-regulates T cell activation genes but up-regulates histone modification genes (Banerjee et al, 2012).…”

Section: Brd4-p-tefb Interaction and Its Effect On Hiv-1 Transcriptiomentioning

confidence: 99%

Mechanism and factors that control HIV-1 transcription and latency activation

Liu

Shao

et al. 2014

J. Zhejiang Univ. Sci. B

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Abstract:After reverse transcription, the HIV-1 proviral DNA is integrated into the host genome and thus subjected to transcription by the host RNA polymerase II (Pol II). With the identification and characterization of human P-TEFb in the late 1990s as a specific host cofactor required for HIV-1 transcription, it is now believed that the elongation stage of Pol II transcription plays a particularly important role in regulating HIV-1 gene expression. HIV-1 uses a sophisticated scheme to recruit human P-TEFb and other cofactors to the viral long terminal repeat (LTR) to produce full-length HIV-1 transcripts. In this process, P-TEFb is regulated by the reversible association with various transcription factors/ cofactors to form several multi-subunit complexes (e.g., 7SK snRNP, super elongation complexes (SECs), and the Brd4-P-TEFb complex) that collectively constitute a P-TEFb network for controlling cellular and HIV-1 transcription. Recent progresses in HIV-1 transcription were reviewed in the paper, with the emphasis on the mechanism and factors that control HIV-1 transcription and latency activation.

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Bromodomain and Extra-terminal (BET) Bromodomain Inhibition Activate Transcription via Transient Release of Positive Transcription Elongation Factor b (P-TEFb) from 7SK Small Nuclear Ribonucleoprotein

Cited by 181 publications

References 39 publications

H3K27 Demethylation at the Proviral Promoter Sensitizes Latent HIV to the Effects of Vorinostat in Ex Vivo Cultures of Resting CD4 ⁺ T Cells

H3K27 Demethylation at the Proviral Promoter Sensitizes Latent HIV to the Effects of Vorinostat in Ex Vivo Cultures of Resting CD4 ⁺ T Cells

Cyclin-Dependent Kinase 12 Increases 3′ End Processing of Growth Factor-Induced c-FOS Transcripts

Mechanism and factors that control HIV-1 transcription and latency activation

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Bromodomain and Extra-terminal (BET) Bromodomain Inhibition Activate Transcription via Transient Release of Positive Transcription Elongation Factor b (P-TEFb) from 7SK Small Nuclear Ribonucleoprotein

Cited by 181 publications

References 39 publications

H3K27 Demethylation at the Proviral Promoter Sensitizes Latent HIV to the Effects of Vorinostat in Ex Vivo Cultures of Resting CD4 + T Cells

H3K27 Demethylation at the Proviral Promoter Sensitizes Latent HIV to the Effects of Vorinostat in Ex Vivo Cultures of Resting CD4 + T Cells

Cyclin-Dependent Kinase 12 Increases 3′ End Processing of Growth Factor-Induced c-FOS Transcripts

Mechanism and factors that control HIV-1 transcription and latency activation

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H3K27 Demethylation at the Proviral Promoter Sensitizes Latent HIV to the Effects of Vorinostat in Ex Vivo Cultures of Resting CD4 ⁺ T Cells

H3K27 Demethylation at the Proviral Promoter Sensitizes Latent HIV to the Effects of Vorinostat in Ex Vivo Cultures of Resting CD4 ⁺ T Cells