Advertisement

 

 

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

Crosstalk between histone modifications indicates that inhibition of arginine methyltransferase CARM1 activity reverses HIV latency.
Author Information (click to view)

Zhang Z, Nikolai BC, Gates LA, Jung SY, Siwak EB, He B, Rice AP, O'Malley BW, Feng Q,


Zhang Z, Nikolai BC, Gates LA, Jung SY, Siwak EB, He B, Rice AP, O'Malley BW, Feng Q, (click to view)

Zhang Z, Nikolai BC, Gates LA, Jung SY, Siwak EB, He B, Rice AP, O'Malley BW, Feng Q,

Advertisement
Share on FacebookTweet about this on TwitterShare on LinkedIn

Nucleic acids research 45(16) 9348-9360 doi 10.1093/nar/gkx550

Abstract

In eukaryotic cells, the gene expression status is strictly controlled by epigenetic modifications on chromatin. The repressive status of chromatin largely contributes to HIV latency. Studies have shown that modification of histone H3K27 acts as a key molecular switch for activation or suppression of many cellular genes. In this study, we found that K27-acetylated histone H3 specifically recruited Super Elongation Complex (SEC), the transcriptional elongation complex essential for HIV-1 long terminal repeat (LTR)-mediated and general cellular transcription. Interestingly, H3K27 acetylation further stimulates H3R26 methylation, which subsequently abrogates the recruitment of SEC, forming a negative feedback regulatory loop. Importantly, by inhibiting methyltransferase activity of CARM1, the enzyme responsible for H3R26 methylation, HIV-1 transcription is reactivated in several HIV latency cell models, including a primary resting CD4+ T cell model. When combined with other latency disrupting compounds such as JQ1 or vorinostat/SAHA, the CARM1 inhibitor achieved synergistic effects on HIV-1 activation. This study suggests that coordinated and dynamic modifications at histone H3K27 and H3R26 orchestrate HIV-1 LTR-mediated transcription, and potentially opens a new avenue to disrupt latent HIV-1 infection by targeting specific epigenetic enzymes.

Submit a Comment

Your email address will not be published. Required fields are marked *

2 × one =

[ HIDE/SHOW ]