miRNAs are critical for the regulation of RAG expression and secondary Ig rearrangement in peripheral B lymphocytes
Bibliographic record
Abstract
Abstract The differential expression of miRNAs throughout B cell development suggests that these ncRNAs contribute to stage-specific regulation of the intricate transcriptional program during B cell development. Conditional ablation of Dicer or deletion of the miR-17~92 cluster in early pro-B cells, revealed a critical role of miRNAs in B cell differentiation. In the present study we compare the phenotypes of mice in which enzymes critical for miRNA biogenesis, Dicer, Drosha and DGCR8 are conditionally ablated in B lymphocytes, allowing us to definitively explore the role of miRNAs in B cell development and function. Global ablation of miRNAs in B lymphocytes lead to an early block in B cell development. Rescue of B cell surviva by overexpression of the anti-apopotic factor Bcl2 revealed that in the absence of miRNAs, B cells in the periphery expressed low levels of Ig heavy chain without expressing light chain. We demonstrate that miRNA-deficient B cells fail to regulate recombination machinery in the periphery, resulting in ongoing Ig light chain gene rearrangement. In addition to the upregulation of RAG1/2 in peripheral B cells, we demonstrated ongoing DNA double strand breaks at Ig light chain loci and upregulation of surrogate light chain components. We show that these events occur downstream of deregulated PI3K signaling and we recapitulate many of these defects in wild-type B lymphocytes by targeting individual components of PI3K signaling network. Furthermore, we achieve complete rescue of miRNA deficient B cells when we introduce a pro-survival Bcl2 transgene along with an Ig transgene resistant to light chain editing. Our data highlight an important and novel role for miRNAs in the maintenance of a mature phenotype in peripheral B cells.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".