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Inhibition of the H3K27 demethylase UTX enhances the epigenetic silencing of HIV proviruses and induces HIV-1 DNA hypermethylation but fails to permanently block HIV reactivation.

ABSTRACT: One strategy for a functional cure of HIV-1 is "block and lock", which seeks to permanently suppress the rebound of quiescent HIV-1 by epigenetic silencing. For the bivalent promoter in the HIV LTR, both histone 3 lysine 27 tri-methylation (H3K27me3) and DNA methylation are associated with viral suppression, while H3K4 tri-methylation (H3K4me3) is correlated with viral expression. However, H3K27me3 is readily reversed upon activation of T-cells through the T-cell receptor. In an attempt to suppress latent HIV-1 in a stable fashion, we knocked down the expression or inhibited the activity of UTX/KDM6A, the major H3K27 demethylase, and investigated its impact on latent HIV-1 reactivation in T cells. Inhibition of UTX dramatically enhanced H3K27me3 levels at the HIV LTR and were associated with increased DNA methylation. In latently infected cells from patients, GSK-J4, which is a potent dual inhibitor of the H3K27me3/me2-demethylases JMJD3/KDM6B and UTX/KDM6A, effectively suppressed the reactivation of latent HIV-1 and also induced DNA methylation at specific sites in the 5'LTR of latent HIV-1 by the enhanced recruitment of DNMT3A to HIV-1. Nonetheless, suppression of HIV-1 through epigenetic silencing required the continued treatment with GSK-J4 and was rapidly reversed after removal of the drug. DNA methylation was also rapidly lost after removal of drug, suggesting active and rapid DNA-demethylation of the HIV LTR. Thus, induction of epigenetic silencing by histone and DNA methylation appears to be insufficient to permanently silence HIV-1 proviral transcription.

SUBMITTER: Nguyen K

PROVIDER: S-EPMC8562785 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Epigenome alteration in chondrocytes correlates with osteoarthritis (OA) development. H3K27me3 demethylase UTX regulates tissue homeostasis and deterioration, while its role was not yet studied in articulating joint tissue in situ. We now uncovered that increased UTX and H3K27me3 expression in articular chondrocytes positively correlated with human knee OA. Forced UTX expression upregulated the H3K27me3 enrichment at transcription factor Sox9 promoter, inhibiting key extracellular matrix molecules collagen II, aggrecan, and glycosaminoglycan in articular chondrocytes. Utx overexpression in knee joints aggravated the signs of OA, including articular cartilage damage, synovitis, osteophyte formation, and subchondral bone loss in mice. Chondrocyte-specific Utx knockout mice developed thicker articular cartilage than wild-type mice and showed few gonarthrotic symptoms during destabilized medial meniscus- and collagenase-induced joint injury. In vitro, Utx loss changed H3K27me3-binding epigenomic landscapes, which contributed to mitochondrial activity, cellular senescence, and cartilage development. Insulin-like growth factor 2 (Igf2) and polycomb repressive complex 2 (PRC2) core components Eed and Suz12 were, among others, functional target genes of Utx. Specifically, Utx deletion promoted Tfam transcription, mitochondrial respiration, ATP production and Igf2 transcription but inhibited Eed and Suz12 expression. Igf2 blockade or forced Eed or Suz12 expression increased H3K27 trimethylation and H3K27me3 enrichment at Sox9 promoter, compromising Utx loss-induced extracellular matrix overproduction. Taken together, UTX repressed articular chondrocytic activity, accelerating cartilage loss during OA. Utx loss promoted cartilage integrity through epigenetic stimulation of mitochondrial biogenesis and Igf2 transcription. This study highlighted a novel noncanonical role of Utx, in concert with PRC2 core components, in controlling H3K27 trimethylation and articular chondrocyte anabolism and OA development.

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Inhibition of the H3K27 demethylase UTX enhances the epigenetic silencing of HIV proviruses and induces HIV-1 DNA hypermethylation but fails to permanently block HIV reactivation.

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