HDAC2 inhibition restores H4K16 Acetylation and Rescues Cellular Senescence in Hutchinson-Gilford progeria syndrome
Bibliographic record
Abstract
Summary Histone H4 lysine 16 acetylation (H4K16ac) controls chromatin compaction, replication-coupled chromatin maturation and double-strand break repair, and is depleted in Hutchinson–Gilford progeria syndrome (HGPS) vascular smooth muscle cells (VSMCs). To identify the enzymes that set steady-state H4K16ac, we depleted KAT5, KAT8, all eleven zinc-dependent HDACs and all seven sirtuins in HeLa and U2OS cells, then in unaffected control and HGPS VSMCs. KAT8 depletion markedly reduced H4K16ac; KAT5 depletion had little effect. Among erasers, HDAC2 was dominant: its depletion or overexpression bidirectionally modulated H4K16ac, HDAC1 did neither, and SIRT1 depletion raised H4K16ac in these lines but far less in HGPS VSMCs. HDAC2-directed inhibitors (BRD4884, MI192, Santacruzamate A) restored H4K16ac in HGPS VSMCs, whereas the SIRT1 inhibitor EX527 did not. They also improved nuclear architecture, reduced γH2AX signaling, preserved Ki67 positivity across serial passage, and limited senescence-associated β-galactosidase accumulation. HDAC2 is therefore the predominant class I regulator of steady-state H4K16ac and a candidate target for limiting senescence in HGPS VSMCs.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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) | 0.002 | 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".