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LINE1 elements at distal junctions of rDNA repeats regulate nucleolar organization in human embryonic stem cells
Genes & Development ( IF 7.5 ) Pub Date : 2024-12-20 , DOI: 10.1101/gad.351979.124 Lamisa Ataei, Juan Zhang, Simon Monis, Krystyna Giemza, Kirti Mittal, Joshua Yang, Mayu Shimomura, Brian McStay, Michael D. Wilson, Miguel Ramalho-Santos
Genes & Development ( IF 7.5 ) Pub Date : 2024-12-20 , DOI: 10.1101/gad.351979.124 Lamisa Ataei, Juan Zhang, Simon Monis, Krystyna Giemza, Kirti Mittal, Joshua Yang, Mayu Shimomura, Brian McStay, Michael D. Wilson, Miguel Ramalho-Santos
The nucleolus is a major subnuclear compartment where ribosomal DNA (rDNA) is transcribed and ribosomes are assembled. In addition, recent studies have shown that the nucleolus is a dynamic organizer of chromatin architecture that modulates developmental gene expression. rDNA gene units are assembled into arrays located in the p-arms of five human acrocentric chromosomes. Distal junctions (DJs) are ∼400 kb sequences adjacent to rDNA arrays that are thought to anchor them at the nucleolus, although the underlying regulatory elements remain unclear. Here we show that DJs display a dynamic chromosome conformation profile in human embryonic stem cells (hESCs). We identified a primate-specific, full-length insertion of the retrotransposon long interspersed nuclear element 1 (LINE1) in a conserved position across all human DJs. This DJ-LINE1 locus interacts with specific regions of the DJ and is upregulated in naïve hESCs. CRISPR-based deletion and interference approaches revealed that DJ-LINE1 contributes to nucleolar positioning of the DJs. Moreover, we found that the expression of DJ-LINE1 is required for maintenance of the structure and transcriptional output of the nucleolus in hESCs. Silencing of DJ-LINE1 leads to loss of self-renewal, disruption of the landscape of chromatin accessibility, and derepression of earlier developmental programs in naïve hESCs. This work uncovers specific LINE1 elements with a fundamental role in nucleolar organization in hESCs and provides new insights into how the nucleolus functions as a key genome-organizing hub.
更新日期：2024-12-20
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