The Short Isoform of BRD4 Promotes HIV-1 Latency by Engaging Repressive SWI/SNF Chromatin-Remodeling Complexes

• Published in: Molecular cell Vol. 67; no. 6; pp. 1001 - 1012.e6
• Main Authors: Conrad, Ryan J., Fozouni, Parinaz, Thomas, Sean, Sy, Hendrik, Zhang, Qiang, Zhou, Ming-Ming, Ott, Melanie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.09.2017
• Subjects: Azepines - pharmacology; BET protein; BRD4; BRG1; bromodomain; chromatin; Chromatin - genetics; Chromatin - metabolism; Chromatin Assembly and Disassembly - drug effects; Chromatin Immunoprecipitation; Chromosomal Proteins, Non-Histone - drug effects; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - metabolism; DNA Helicases - genetics; DNA Helicases - metabolism; DNA, Viral - genetics; DNA, Viral - metabolism; Dose-Response Relationship, Drug; Down-Regulation; gene expression; Gene Expression Regulation, Viral; genomics; HEK293 Cells; High-Throughput Nucleotide Sequencing; HIV; HIV-1 - drug effects; HIV-1 - genetics; HIV-1 - immunology; HIV-1 - metabolism; Host-Pathogen Interactions; Human immunodeficiency virus 1; Humans; JQ1; Jurkat Cells; latency; LTR; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; nucleosomes; precipitin tests; Promoter Regions, Genetic; Protein Binding; Protein Isoforms; protein subunits; Retroelements; retrotransposons; RNA Interference; SWI/SNF; T-lymphocytes; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - virology; terminal repeat sequences; Time Factors; transcription (genetics); Transcription Factors - drug effects; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic - drug effects; Transfection; Triazoles - pharmacology; Virus Latency - drug effects; bromodomain; BET protein; HIV; BRG1; latency; SWI/SNF; JQ1; LTR; chromatin; BRD4
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2017.07.025

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. [Display omitted] •The short isoform of BRD4 is a corepressor of HIV transcription during latency•BET inhibition disrupts SWI/SNF nucleosome remodelers at the latent HIV promoter•Short BRD4 directly binds the BRG1 ATPase to tether SWI/SNF to latent HIV chromatin•Endogenous LTR-containing retroelements are co-occupied by BRD4 and BRG1 BET protein inhibition can reverse HIV latency, yet the long isoform of BRD4 is a well-characterized transcriptional co-activator. Conrad et al. find that the short isoform of BRD4 cooperates with SWI/SNF nucleosome remodelers to repress HIV transcription during latency, a phenotype reversed by BET inhibitor treatment.