A143 ENTEROID CELL DIFFERENTIATION IS UNDER class I HDAC CONTROL
Bibliographic record
Abstract
Deacetylases HDAC1 and HDAC2 are epigenetic erasers of acetyl marks on histones and transcription factors, among others, and thus regulate gene expression, cell proliferation and differentiation. We have shown that, in contrast to subtle defects upon Hdac1 or Hdac2 specific IEC-induced deletion in mice, dual Hdac1 and Hdac2 deletion alters intestinal epithelial cell (IEC) growth and differentiation, leading to chronic colonic inflammation. In addition, in contrast to single Hdac1 or Hdac2 deletion, dual Hdac1 and Hdac2 deletion results in enteroid growth defects. In this work, we investigated whether Hdac1 or Hdac2 modify IEC-specific gene and protein expression programs, as well as differentiation pathways, in enteroids through common and/or different pathways. Jejunal villin-Cre Hdac1 or Hdac2 enteroids were grown in medium with or without SILAC, for proteome quantification by mass spectrometry. The transcriptome was assessed by RNA-Seq. Top Canonical Pathways were identified by IPA bioinformatics analysis. The phenotype of Hdac1- and Hdac2-deleted enteroids was determined by 1) microscopy; 2) HDAC activity measurements; 3) Alcian blue (goblet cells) and Best Carmine (Paneth cells) staining, 4) γ-H2AX immunohistochemistry, and 5) qPCR or Western blot analysis of selected differentiation markers, or HDAC1- or HDAC2-specific targets identified by RNA-Seq. Transcriptomic analysis revealed shared (FXR/RXR activation) and distinct (LXR/RXR activation, HDAC1; Retinoate biosynthesis, HDAC2) Top Canonical Pathways. Proteomic analysis revealed common (LPS/IL-1 mediated inhibition of RXR function) and different (Fatty acid oxidation, HDAC1; Aryl hydrocarbon receptor signaling, HDAC2) Top Canonical Pathways, among others. HDAC activity was slightly decreased in Hdac1- or Hdac2-deleted enteroids. Increased DNA damage was observed, as assessed by γ-H2AX staining. Both Hdac1- or Hdac2-deleted enteroids displayed augmented bud numbers, as well as increased numbers of goblet and intermediate cells, as determined by Alcian blue and Best Carmine staining. This correlated with increased expression of differentiation markers. qPCR analysis uncovered metabolic and inflammatory genes commonly regulated by HDAC1 and HDAC2 (Nox1, Il18, Hmgcs2) or specifically regulated by HDAC1 (St3gal4) or HDAC2 (Muc3). HDAC1 and HDAC2 independently regulate enteroid differentiation and behavior by common and select pathways. In addition, HDAC1 and HDAC2 may selectively regulate IEC-intrinsic metabolic and environmental responses through a subset of differentially regulated genes dependent on their action. Selective pharmacological inhibition of HDAC1 or HDAC2 activity could be advantageous to control altered metabolic and inflammatory pathways in IEC and in the intestinal environment. CCC
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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) | 0.004 | 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".