A LINE1-Nucleolin Partnership Regulates Early Development and ESC Identity

Abstract

Summary Transposable elements represent nearly half of mammalian genomes and are generally described as parasites or ‘junk DNA’. The LINE1 retrotransposon is the most abundant class and is thought to be deleterious for cells, yet is paradoxically highly expressed during early development. Here we report that LINE1 plays essential roles in mouse embryonic stem (ES) cells and pre-implantation embryos. In ES cells, LINE1 acts as a nuclear RNA scaffold that recruits Nucleolin and Kap1/Trim28 to repress Dux, the master activator of a transcriptional program specific to the 2-cell embryo. In parallel, LINE1 RNA mediates binding of Nucleolin and Kap1 to rDNA, promoting rRNA synthesis and ES cell self-renewal. In embryos, LINE1 RNA is required for Dux silencing, synthesis of rRNA and exit from the 2-cell stage. The results reveal an essential partnership between LINE1 RNA, Nucleolin, Kap1 and peri-nucleolar chromatin in the regulation of transcription, developmental potency and ES cell self-renewal.

A lncRNA-like Role for LINE1s in Development

“…The latter paper utilized KRAB-domain fused transcription activator-like effectors (TALEs). Percharde et al (2018) recapitulate Jachowicz’s finding that LINE1 is needed to induce global chromatin condensation. They go further, however, demonstrating lncRNA-like roles for LINE1 RNA in ESC self-renewal and preimplantation development.…”

“…In a recent paper, Percharde et al (2018) identify a lncRNA-like function for LINE1 transposable elements in regulating gene expression to facilitate embryonic stem cell self-renewal and preimplantation development. …”

“…Few studies, however, have evaluated the role of TE transcripts in cellular processes. In a recent issue of Cell , Percharde et al (2018) used antisense oligos as a tool to deplete long interspersed nuclear element 1 (LINE1) transcripts in embryonic stem cells (ESCs) and preimplantation mouse embryos as a complementary but distinct approach to the transcriptional silencing of LINE1 recently performed by Jachowicz et al (2017). The latter paper utilized KRAB-domain fused transcription activator-like effectors (TALEs).…”

“…Numerous studies have reported high levels of LINE1 RNA expression in embryos and germ cells despite relatively low levels of retrotransposition (Richardson et al, 2017). Percharde et al (2018) employed an antisense oligo strategy to deplete LINE1 RNA in mouse ESCs (mESCs). LINE1 knockdown (KD) ESC cultures proliferated more slowly and had fewer cells in S phase, indicating an important role for LINE1 in self-renewal (Figure 1A).…”

“…The work from Percharde et al (2018) suggests that LINE1 elements have also evolved critical functions as lncRNAs in early development. By binding Nucleolin and KAP1, LINE1 elements facilitate both the activation of rDNA genes and the suppression of many 2C genes via silencing of Dux .…”