1. The Short Isoform of BRD4 Promotes HIV-1 Latency by Engaging Repressive SWI/SNF Chromatin-Remodeling Complexes
- Author
-
Conrad, Ryan J, Fozouni, Parinaz, Thomas, Sean, Sy, Hendrik, Zhang, Qiang, Zhou, Ming-Ming, and Ott, Melanie
- Subjects
Medical Microbiology ,Biomedical and Clinical Sciences ,Biological Sciences ,Human Genome ,Infectious Diseases ,HIV/AIDS ,Genetics ,Sexually Transmitted Infections ,2.1 Biological and endogenous factors ,Aetiology ,Infection ,Azepines ,Cell Cycle Proteins ,Chromatin ,Chromatin Assembly and Disassembly ,Chromatin Immunoprecipitation ,Chromosomal Proteins ,Non-Histone ,DNA Helicases ,DNA ,Viral ,Dose-Response Relationship ,Drug ,Down-Regulation ,Gene Expression Regulation ,Viral ,HEK293 Cells ,HIV-1 ,High-Throughput Nucleotide Sequencing ,Host-Pathogen Interactions ,Humans ,Jurkat Cells ,Nuclear Proteins ,Promoter Regions ,Genetic ,Protein Binding ,Protein Isoforms ,RNA Interference ,Retroelements ,T-Lymphocytes ,Time Factors ,Transcription Factors ,Transcription ,Genetic ,Transfection ,Triazoles ,Virus Latency ,BET protein ,BRD4 ,BRG1 ,HIV ,JQ1 ,LTR ,SWI/SNF ,bromodomain ,chromatin ,latency ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
BET proteins commonly activate cellular gene expression, yet inhibiting their recruitment paradoxically reactivates latent HIV-1 transcription. Here we identify the short isoform of BET family member BRD4 (BRD4S) as a corepressor of HIV-1 transcription. We found that BRD4S was enriched in chromatin fractions of latently infected T cells, and it was more rapidly displaced from chromatin upon BET inhibition than the long isoform. BET inhibition induced marked nucleosome remodeling at the latent HIV-1 promoter, which was dependent on the activity of BRG1-associated factors (BAF), an SWI/SNF chromatin-remodeling complex with known repressive functions in HIV-1 transcription. BRD4S directly bound BRG1, a catalytic subunit of BAF, via its bromodomain and extraterminal (ET) domain, and this isoform was necessary for BRG1 recruitment to latent HIV-1 chromatin. Using chromatin immunoprecipitation sequencing (ChIP-seq) combined with assay for transposase-accessible chromatin coupled to high-throughput sequencing (ATAC-seq) data, we found that the latent HIV-1 promoter phenotypically resembles endogenous long terminal repeat (LTR) sequences, pointing to a select role of BRD4S-BRG1 complexes in genomic silencing of invasive retroelements.
- Published
- 2017