The role of LEDGF in transcription is exploited by HIV-1 to position integration [RNA]

HIV-1 integration occurs across actively transcribed genes due to the interaction of integrase with chromatin factor LEDGF. Although LEDGF was originally purified as a co-activator that stimulates promoters, this role is inconsistent with LEDGF-mediated integration across gene bodies and with data indicating LEDGF promotes transcriptional elongation. We found LEDGF is enriched primarily at transcription start sites (TSSs) of active promoters. Additional data shows MLL1 recruits LEDGF to promoters and LEDGF recruits RNA Pol II. Contrary to existing models, we find that integration into genes is independent of interactions between H3K36me3 and the PWWP domain of LEDGF. Instead, it is the level of LEDGF at TSSs that determines gene specificity of integration. These data support a dual role model of LEDGF where it is tethered to promoters by MLL1 and recruits RNA Pol II. Subsequently, LEDGF travels across the sequences of genes to effect HIV-1 integration. Overall design: Poly RNAseq experiment of WT HEK293T and LEDGF-KO cells, with 4 biological replicates