Promoter hijacking by primate LINC00473 disrupts an ancestral CREB-PDE10A feedback loop
Bibliographic record
Abstract
ABSTRACT Thousands of human long noncoding RNAs (lncRNAs) evolved in primates, although much remains unknown about how these lncRNAs shaped human gene regulatory networks. The primate-specific lncRNA gene LINC00473 has a CREB-inducible promoter that is conserved beyond primates and the gene is located upstream of PDE10A, which encodes an inhibitor of CREB. To gain insight into the regulatory consequences of LINC00473 acquisition, we tested the cellular function of the conserved mouse promoter. We found that the homologous mouse promoter is induced by CREB and regulates the downstream Pde10a gene in C2C12 myoblast-like cells and neurons. Activation of this promoter by CRISPRa increased Pde10a transcript and protein levels, and proteomics revealed that elevated Pde10a promoted C2C12 differentiation at the expense of proliferation. Activation of Pde10a by CRISPRa also impaired CREB-dependent gene expression, suggesting that the mouse homolog of the LINC00473 promoter drives a CREB-Pde10a feedback loop. In contrast to the mouse homolog, human LINC00473 promoter activation by CRISPRa increased LINC00473 expression with either no change in PDE10A or delayed induction compared to mice. Our findings suggest that the newly evolved LINC00473 gene hijacked an ancestral CREB-inducible Pde10a promoter, thereby disrupting a negative feedback loop that may otherwise constrain CREB-dependent gene expression. GRAPHICAL ABSTRACT
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".