LEDGF promotes mRNA splicing and targets HIV-1 integration to highly spliced genes

Authors

• PK Singh
• MR Plumb
• AL Ferris
• X Wu
• HJ Fadel
• JR Iben
• EM Poeschla
• SH Hughes
• M Kvaratskhelia
• HL Levin

Abstract

The host chromatin-binding factor LEDGF/p75 interacts with HIV-1 integrase and directs integration to active transcription units. To understand how LEDGF/p75 recognizes transcription units we sequenced one million HIV-1 integration sites isolated from cultured HEK293T cells. Cancer genes were preferentially targeted, raising concerns about using lentivirus vectors for gene therapy. Integration in transcription units showed a strong preference for 5’ sequences. Importantly, we discovered that introns and alternative splicing contributed significantly to integration site selection. These correlations were independent of transcription levels and size of transcription units. The targeting of highly spliced genes was absent in cells lacking LEDGF. Affinity purification showed LEDGF/p75 is associated with splicing factors and RNAseq analysis showed that LEDGF/p75 contributes to splicing patterns in half of the transcription units that have alternative isoforms. Thus, LEDGF/p75 interacts with splicing factors, contributes to splicing, and, directs HIV-1 integration to transcription units that are highly spliced.

Scientific Focus Area: Virology

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