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

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 novel corepressor of HIV-1 transcription. We found that BRD4S was enriched in chromatin fractions of latently infected T cells and 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 BAF, a SWI/SNF chromatin-remodeling complex with known repressive functions in HIV-1 transcription. BRD4S directly bound BRG1, a catalytic subunit of BAF, via its bromo- and ET domains and was necessary for BRG1 recruitment to latent HIV-1 chromatin. Using ChIP-seq combined with ATAC-seq data, we found that the latent HIV-1 promoter phenotypically resembles endogenous LTR sequences, pointing to a select role of BRD4S:BRG1 complexes in genomic silencing of invasive retroelements. ChIP-seq of BRD4, BRG1, and Pol II +/- JQ1, ATAC-seq +/- JQ1, RNA-seq of selective BRD4 isoform knockdown cells in a Jurkat derived model of HIV-1 latency