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Long interspersed element-1 (LINE-1 or L1) makes up 17% of the human genome and continues to produce genetic variants and, in some cases, cause disease. However, the regulation and function of L1 are still poorly understood.
2024年4月10日，清华大学刘念团队在Molecular Cell 在线发表题为“SAFB restricts contact domain boundaries associated with L1 chimeric transcription”的研究论文，该研究发现L1可以富集RNA聚合酶II (RNA Pol II)，表达L1嵌合转录物，并在人类细胞中创建接触结构域边界。
This effect of L1 is limited by nuclear matrix protein scaffold attachment factor B (SAFB), which recognizes transcriptionally active L1 by inhibiting the enrichment of RNA Pol II by binding to L1 transcripts. Acute inhibition of RNA Pol II transcription abolishes domain boundaries associated with L1 chimeric transcripts, suggesting a transcription-dependent mechanism. Deletion of L1 impairs the formation of domain boundaries, while the insertion of L1 during evolution introduces species-specific domain boundaries. The study showed that L1 can produce RNA Pol II-enriched regions, alter genomic organization, and SAFB regulates L1 and RNA Pol II activity to maintain gene regulation.
Long interspersed element-1 (LINE-1 or L1) has been with mammals for more than 150 million years (Ma), and L1 makes up 17% of the human genome, with about 500,000 copies. Most L1s lose transposable activity due to mutations and truncations, but at least 100 L1s can still be mobilized, and many more L1s can be transcribed Transcription of L1 changes in a site-specific manner across different cell types and developmental stages, with L1 transcriptional activity being particularly high during mammalian aging, embryogenesis, neurogenesis, and tumor development. Previous studies have shown that L1 can disrupt host gene expression and transcribe L1-containing chimeric RNAs by providing alternative start, splicing, and termination sites. However, the role of L1 in higher-order genome structure and remote gene regulation remains unclear. The eukaryotic genome is folded into three-dimensional (3D) genomic structures, the characteristics of which can be revealed by genome-wide chromosome conformational capture (Hi-C) studies, including compartments and domains. Compartments, originally defined as multi-base active (A-compartment) and inactive (B-compartment) chromatin regions, have recently been detected at finer scales and are formed due to the self-affinity of biochemically similar chromatin regions. Contact domains or topological association domains (TADs) are mega/submega-based squares on the Hi-C map, and they show rich interactions within them. Contact domains are separated by boundaries that are often colocalized with ccctc binding factor (CTCF) binding sites and transcription start sites (TSSs) of housekeeping genes. However, the exact function and regulation of transcription in boundary formation is unknown. In addition, the nucleus contains many RNA and RNA-binding proteins that interact with chromatin. Previous studies have shown that these RNAs and their binding proteins contribute to condensate formation, nuclear compartmentalization, and genome structure. However, their complex role in three-dimensional genomic organization is still not fully understood.
模式图（Credit: Molecular Cell ）
The study found that L1 can enrich RNA polymerase II (RNA Pol II), transcribe L1 chimeric RNA, and create contact domain boundaries. This process is limited by nuclear matrix protein scaffold attachment factor B (SAFB), which recognizes L1 RNA, aggregates at L1, and reduces RNA Pol II enrichment. In addition, continuous L1 insertion into the genome evolution introduces new domain boundaries, and the intensity of L1-related domain boundaries varies across different cell types and developmental states, which correlates with the enrichment level of RNA Pol II at L1. Overall, the results demonstrate the role of L1 insertions in creating regional boundaries, and SAFB positively counteracts this process to preserve chromatin structure and gene regulation.
Original link https://doi.org/10.1016/j.molcel.2024.03.021
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文章来源|“ iNature"
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