HDAC8-Mediated Epigenetic Reprogramming Plays a Key Role in Resistance to Anthrax Lethal Toxin–Induced Pyroptosis in Macrophages
Bibliographic record
Abstract
Macrophages pre-exposed to a sublethal dose of anthrax lethal toxin (LeTx) are refractory to subsequent high cytolytic doses of LeTx, termed toxin-induced resistance (TIR). A small population of TIR cells (2-4%) retains TIR characteristics for up to 5-6 wk. Through studying these long-term TIR cells, we found that a high level of histone deacetylase (HDAC)8 expression was crucial for TIR. Knocking down or inhibition of HDAC8 by small interfering RNAs or the HDAC8-specific inhibitor PCI-34051, respectively, induced expression of the mitochondrial death genes Bcl2 adenovirus E1B 19 kDa-interacting protein 3 (BNIP3), BNIP3-like and metastatic lymph node 64, and resensitized TIR cells to LeTx. Among multiple histone acetylations, histone H3 lysine 27 (H3K27) acetylation was most significantly decreased in TIR cells in an HDAC8-dependent manner, and the association of H3K27 acetylation with the genomic regions of BNIP3 and metastatic lymph node 64, where HDAC8 was recruited to, was diminished in TIR cells. Furthermore, overexpression of HDAC8 or knocking down the histone acetyltransferase CREB-binding protein/p300, known to target H3K27, rendered wild-type cells resistant to LeTx. As in RAW264.7 cells, primary bone marrow-derived macrophages exposed to a sublethal dose of LeTx were resistant to LeTx in an HDAC8-dependent manner. Collectively, this study demonstrates that epigenetic reprogramming mediated by HDAC8 plays a key role in determining the susceptibility of LeTx-induced pyroptosis in macrophages.
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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) | 0.001 | 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 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".