SAFB restricts contact domain boundaries associated with L1 chimeric transcription

Long interspersed element-1 (LINE-1 or L1) comprises 17% of the human genome, continuously generates genetic variations, and cause disease in certain cases. However, the regulation and function of L1 remain poorly understood. Here, we uncover that L1 can enrich RNA polymerase IIs (Pol IIs), express L1 chimeric transcripts and create contact domain boundaries. This impact of L1 is restricted by a nuclear matrix protein Scaffold Attachment Factor B (SAFB) that recognizes transcriptionally active L1s by binding L1 transcripts to inhibit Pol II enrichment and reduce L1 transcription. Acute inhibition of Pol II transcription abolishes the domain boundaries associated with L1 chimeric transcripts, indicating a transcription-dependent mechanism. Deleting L1 impairs domain boundary formation, and L1 insertions during evolution have introduced species-specific domain boundaries. Our data show that L1 can create Pol II enriched regions that alter genome organization, and that SAFB regulates L1 and Pol II activity to preserve gene regulation.