DNA damage responses from light chain recombination integrate with B cell developmental programs 2141
Bibliographic record
Abstract
Abstract Description In early B cell development, pre-B cells undergo rapid clonal expansion followed by cell cycle arrest and recombination of the immunoglobulin light chain (Igl) genes. Igl rearrangement generates programmed DNA double-stranded breaks (DSBs) by the RAG endonuclease. RAG DSBs trigger canonical DNA damage responses (DDRs) for repair and unique non-canonical DDRs (ncDDRs) that integrate with developmental signaling. We have identified that ncDDRs activate SPIC/BCLAF1, a transcription factor complex, which suppresses the pro-proliferative kinase SYK. Using novel SYK- and SPIC-reporter mice, we find dynamic changes in SYK expression associated with ncDDR activation in small pre-B cells in vivo. We show DDRs are induced in SYK-high small pre-B cells with initiation of Igl rearrangement and SYK is subsequently suppressed in conjunction with resolution of DDRs. Additionally, we find increased BCLAF1 and concomitantly reduced PU.1 binding genome-wide and at the Syk promoter in pre-B cells with high ncDDR signaling. Single-cell RNA sequencing reveals BCLAF1 loss results in increased pre-B cell proliferation and disrupted developmental progression. Currently, we are using VDJ-sequencing to define the impact of BCLAF1’s role in maintaining cell cycle arrest and developmental integrity on the rate of successful Igl rearrangement and the genetic diversity of mature B cell receptors. These findings establish critical and novel roles for DNA damage responses in B cell development. Funding Sources NIH/NIAD R56AI153234; NIH/NIAID R01AI173077; NIH/NIAID R21AI166259; NIH/NIAID 2T32AI007163-46; Hyundai Hope on Wheels; St. Louis; Children’s Hospital Foundation; Children’s Discovery Institute Topic Categories Hematopoiesis and Immune System Development (HEM)
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
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".