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 andcreate contact domain boundaries in human cells. This impact of L1 is restricted by anuclear matrix protein Scaffold Attachment Factor B (SAFB) that recognizes transcriptionally active L1s by binding L1 transcripts to inhibit Pol II enrichment. Acute inhibition of Pol II transcription abolishes the domain boundaries associated with L1 chimeric transcripts, indicating a transcription-dependent mechanism. Deleting L1impairs 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，LINE-1，简称L1）占人类基因组的17%，可持续产生遗传变异，且在特定情况下会引发疾病。然而，目前学界对L1的调控机制与生物学功能仍知之甚少。本研究发现，L1可在人类细胞中富集RNA聚合酶II（RNA polymerase II，Pol II）、转录产生L1嵌合转录本，并构建染色质接触域边界。L1的上述生物学作用可被核基质蛋白支架附着因子B（Scaffold Attachment Factor B，SAFB）所抑制：SAFB可结合转录活跃的L1转录本，识别此类L1元件并阻断Pol II的富集过程。对Pol II转录的急性抑制可消除与L1嵌合转录本相关的染色质域边界，这表明该调控机制依赖于转录过程。敲除L1元件会损害染色质域边界的形成，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域边界。本研究数据表明，L1可构建富集Pol II的基因组区域，从而改变基因组三维组织结构；同时SAFB可通过调控L1与Pol II的活性，维持正常的基因表达调控。