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.

长散在核元件-1（Long interspersed element-1）占人类基因组的17%，可持续产生遗传变异，在特定情况下还会引发疾病。然而，学界对L1的调控机制与生物学功能仍知之甚少。本研究揭示，L1可富集RNA聚合酶II（RNA polymerase II）、表达L1嵌合转录本，并构建染色质接触结构域边界。L1的上述调控效应可被核基质蛋白支架附着因子B（Scaffold Attachment Factor B，SAFB）所抑制：SAFB可结合L1转录本以识别转录活跃的L1，进而抑制RNA聚合酶II的富集并降低L1的转录水平。对RNA聚合酶II转录的急性抑制可消除与L1嵌合转录本相关的结构域边界，表明该调控机制依赖于转录过程。敲除L1会破坏结构域边界的形成，而进化过程中发生的L1插入事件则引入了物种特异性的染色质结构域边界。本研究数据证实，L1可构建富集RNA聚合酶II的染色质区域，进而改变基因组三维组织结构；同时SAFB可通过调控L1与RNA聚合酶II的活性，维持正常的基因表达调控。