HDAC2 inhibition restores H4K16 Acetylation and Rescues Cellular Senescence in Hutchinson-Gilford progeria syndrome
Bibliographic record
Abstract
Abstract Histone H4K16 acetylation (H4K16ac) is a key epigenetic mark essential for chromatin structure and DNA repair, which is substantially reduced in the accelerated aging disorder Hutchinson-Gilford progeria syndrome (HGPS). The specific enzymes governing H4K16ac homeostasis, particularly the deacetylase responsible for its loss in HGPS, remain poorly defined. Here, we sought to identify the enzymes regulating H4K16ac and determine if their inhibition could rescue HGPS-associated cellular defects. Using systematic siRNA screening in HeLa and U2OS cells, we confirmed that KAT8/MOF is the principal H4K16 acetyltransferase. Surprisingly, we identified HDAC2 as the dominant class I histone deacetylase for H4K16ac; knockdown of the highly homologous HDAC1 had no effect. While SIRT1 knockdown also increased H4K16ac, its contribution was minimal in HGPS vascular smooth muscle cells (VSMCs) compared to HDAC2. Crucially, selective pharmacological inhibition of HDAC2, but not SIRT1, robustly restored H4K16ac levels in HGPS VSMCs. This restoration led to a significant rescue of premature aging phenotypes, including improvements in nuclear morphology, preservation of proliferative capacity (Ki67) at late passages, and a significant reduction in cellular senescence. The effects of HDAC2 inhibition on cellular senescence and nuclear morphology suggests that HDAC2-mediated histone deacetylation contributes directly to the pathological features of HGPS, extending the functional impact of HDAC2 inhibition beyond DNA repair defects to fundamental aspects of cellular aging.
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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 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.002 | 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".