Fig. 9: The role of BRD4 in HIV-1 transcription in LEDGF/p75-dependent and LEDGIN-retargeted provirus.
From: BRD4 modulator ZL0580 and LEDGINs additively block and lock HIV-1 transcription
BRD4 affects HIV-1 transcription at multiple levels. (1) BRD4 is a negative regulator of Tat-dependent transcription. BRD4 is bound to acetylated histones and competitively blocks the interaction of Tat with P-TEFβ preventing the formation of the Super elongation complex (SEC). (2) BRD4 is a positive regulator of Tat-independent transcription because BRD4 recruits P-TEFβ to the viral promotor. (3) BRD4 blocks HIV-1 transcription through BRG1. The short isoform of BRD4, lacking a P-TEFb interaction domain, directly binds BRG1 and acetylated histones, resulting in a recruitment of BRG1 to the HIV-1 promotor. BRG1 is a catalytical subunit of BAF, a SWI/SNF chromatin-remodeling complex which induces a repressive promotor nucleosome position. (4) BRD4 mediates enhancer-dependent transcription in trans leading to the further recruitment of P-TEFβ, Med1 and transcription factors (TFs). b LEDGF/p75 contains an IBD that binds the viral IN and a PWWP domain that binds the active chromatin mark, H3K36me2/3. LEDGF/p75 targets integration into active genes. Active transcription can also result from a stochastic integration near enhancer regions (with H3K27ac or H3K4me1 as marks), independent of LEDGF/p75 but dependent on BRD4. LEDGINs bind the LEDGF/p75 binding pocket of the viral integrase and retarget integration away from H3K36me2/3 into repressive chromatin regions but do not influence the proximity of integration near enhancer regions. Residual active transcription after LEDGIN-treatment may be caused by integration near enhancers. BRD4 modulators, like JQ1 and ZL0580, may silence enhancer-dependent transcription after LEDGIN-treatment. Figure adapted from41 and created in BioRender. Van belle, S. (2025) https:// BioRender.com/3jlc8r. Ac, acetylated; BAF, brahma associated factor; BRD4L, bromodomain containing protein 4 long isoform; BRD4S, bromodomain containing protein 4 short isoform; BRG1, brahma related gene 1; CTD, carboxy terminal domain; ELLII, elongation factor for RNA Pol II; IBD, integrase binding domain; IN, integrase; Med1, mediator complex subunit 1; pol, polymerase; PIC, pre-integration complex; P-TEFβ, positive transcription elongation factor β; SEC, super elongation complex; TAR, trans-activation response element; Tat, trans-activator of transcription; TF, transcription factors; 7SK snRNP, 7SK small nuclear ribonucleoprotein.
