LINE1 promotes nuclear compartmentalization to repress the 8-cell state in embryonic stem cells
Bibliographic record
Abstract
Summary The family of LINE1 transposable elements underwent a massive expansion in mammalian genomes. While traditionally viewed as a mutagenic selfish element, recent studies point to roles for LINE1 in early mouse development, T cell quiescence and neurogenesis. Here we show that human LINE1 RNA is essential for self-renewal and identity of human embryonic stem cells (hESCs). Silencing of LINE1 using either antisense oligonucleotides or CRISPR interference in naïve hESCs leads to a strong induction of 8C-like cells (8CLCs). We found that genes derepressed upon LINE1 KD are not uniformly distributed across the genome, with an enrichment for chromosome 19, which includes key markers of the 8C state such as TPRX1 . Silencing of TPRX1 , but not other putative 8C regulators p53 or H3.XY , suppresses the induction of the 8C program in LINE1 KD hESCs. We found that LINE1 RNA is preferentially localized to the lamina and periphery of the nucleolus in hESCs. Sequencing of Lamina-Associated Domains (LADs) and Nucleolus-Associated Domains (NADs) reveals a preferential association of chromosome 19 with NADs in hESCs. However, 8CLCs have a distinct nucleolar morphology and a lower association of chromosome 19 and TPRX1 loci with the nucleolus relative to naïve and primed hESCs, suggesting a role for nucleolar dynamics in the 8CLC-hESC transition. In agreement, LINE1 KD leads to disruption of nucleolar architecture with signs of nucleolar stress. Independent perturbations of the nucleolus induce the 8C program in hESCs. Genes induced by LINE1 KD are enriched for targets of Polycomb Repressive Complex (PRC2), and inhibition of PRC2 leads to a strong induction of 8C genes. Our results indicate that LINE1 coordinates nuclear compartmentalization and chromatin-mediated gene repression to prevent developmental reversion of hESCs. Highlights Knockdown of LINE1 induces TPRX1-dependent emergence of 8C-like cells in hESCs. Genes de-repressed upon LINE1 KD are enriched for Chr 19 and PRC2 targets. 8CLCs display dissociation of Chromosome 19 from the nucleolus. Disruption of the nucleolus or inhibition of PRC2 strongly induce the 8C program.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".