Abstract 6411: The histone H3 E97K oncohistone creates a cellular histone H3 deficit and disrupts nucleosome stability
Bibliographic record
Abstract
Abstract Background: Histones are essential components of nucleosomes that regulate chromatin structure and DNA access. Mutations in histones have been implicated in various cancers. Analysis of cancer samples from cBioPortal revealed mutations across all histones, with one "hot spot", the E to K mutation of amino acid 97 on canonical H3, H3.1E97K, found most frequently in patients with lung and genitourinary cancers. Studies with yeast and mammalian cells have shown that this mutation increases histone dimer exchange, decreases nucleosome stability, and impairs yeast growth. However, it remains unclear how this mutation affects cell growth, cell survival, and whether it drives cancer development. Methods: Molecular dynamics simulations was used to identify atomic-level changes in nucleosome interactions between wild-type H3 and H3E97K nucleosomes. Minigenes of HA-tagged H3 and H3E97K retaining their native promoter and 3’ UTR regulatory region was constructed, ensuring expression strictly controlled and coupled with cell cycle progression. Using CRISPR-Cas9 mediated gene editing was used to generate pairs of isogenic human bronchial epithelial cell lines, where one canonical H3 genes, H3.1C11, was tagged with HA, and the E to K mutation was introduced. Western blotting examined protein stability, and immunostaining provided information on cellular localization. CUT & RUN was used to determine the genome-wide distribution of mutant H3E97K histones, while RNA-seq and ATAC-seq identified changes in gene expression and chromatin accessibility. Results: Molecular dynamics simulations showed that the H3E97K mutation disrupted a hydrogen bond network on H3, and interaction with H2AQ104. These changes distorted the orientation of the N-αHelix of H3, destabilizing interaction with the nucleosomal DNA and increasing DNA unwrapping. HA immunoblot reveled that the mutant protein was expressed at only 10% of wild-type level which would lead to a cellular deficit of Histone H3. Bortezomib treatment significantly increased the stability of the mutant H3, indicating the involvement of the proteasome-mediated protein degradation pathway in the instability of H3E97K. Consistently, the mutant Histone H3 was poorly incorporated into nucleosomes with a significant fraction retained in the cytoplasm. Nevertheless, CUT&RUN and immunostaining indicated some of the H3 mutant could be incorporated into chromatin, resulting in altered chromatin accessibility and altered gene expression patterns. Conclusions: The H3E97K oncohistone destabilizes nucleosomes and creates a histone deficit, leading to altered chromatin dynamics and dysregulated gene expression. These changes may promote oncogenesis, highlighting the significance of this mutation in cancer biology.AI was used for editing. Citation Format: Jixiu Shan, Richard L. Bennett, Pierre Priam, Kimberly N. Pereira, Shuxiang Li, James Rober, Maria Aristizabal, Anna R. Panchenko, Jonathan D. Licht. The histone H3 E97K oncohistone creates a cellular histone H3 deficit and disrupts nucleosome stability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6411.
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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) | 0.004 | 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".