Crosstalk between histone modifications indicates that inhibition of arginine methyltransferase CARM1 activity reverses HIV latency
| Autor: | Andrew P. Rice, Zheng Zhang, Edward B. Siwak, Bryan C. Nikolai, Sung Yun Jung, Bert W. O'Malley, Qin Feng, Bin He, Leah A. Gates |
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| Rok vydání: | 2017 |
| Předmět: |
Gene Expression Regulation
Viral 0301 basic medicine Protein-Arginine N-Methyltransferases Transcription Elongation Genetic Methyltransferase CARM1 Benzylidene Compounds Methylation Cell Line Histones 03 medical and health sciences Histone H3 Genetics medicine Humans Epigenetics Enzyme Inhibitors Vorinostat Piperidones HIV Long Terminal Repeat biology Gene regulation Chromatin and Epigenetics Acetylation Virus Latency 3. Good health Chromatin Cell biology Histone Code 030104 developmental biology Histone HIV-1 biology.protein Transcription Factors medicine.drug |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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