14-3-3ζ allows for adipogenesis by modulating chromatin accessibility during the early stages of adipocyte differentiation
Bibliographic record
Abstract
OBJECTIVE: We previously established the scaffold protein 14-3-3ζ as a critical regulator of adipogenesis and adiposity, but whether 14-3-3ζ exerted its regulatory functions in mature adipocytes or in adipose progenitor cells (APCs) remained unclear. METHODS: To decipher which cell type accounted for 14-3-3ζ-regulated adiposity, adipocyte- (Adipoq14-3-3ζKO) and APC-specific (Pdgfra14-3-3ζKO) 14-3-3ζ knockout mice were generated. To further understand how 14-3-3ζ regulates adipogenesis, Tandem Affinity Purification (TAP)-tagged 14-3-3ζ-expressing 3T3-L1 preadipocytes (TAP-3T3-L1) were generated with CRISPR-Cas9, and affinity proteomics was used to examine how the nuclear 14-3-3ζ interactome changes during the initial stages of adipogenesis. ATAC-seq was used to determine how 14-3-3ζ depletion modulates chromatin accessibility during differentiation. RESULTS: We show a pivotal role for 14-3-3ζ in APC differentiation, whereby male and female Pdgfra14-3-3ζKO mice displayed impaired or potentiated weight gain, respectively, as well as fat mass. Proteomics revealed that regulators of chromatin remodeling, like DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1), were significantly enriched in the nuclear 14-3-3ζ interactome and their activities were impacted upon 14-3-3ζ depletion. Enhancing DNMT activity with S-Adenosyl methionine rescued the differentiation of 14-3-3ζ-depleted 3T3-L1 cells. ATAC-seq revealed that 14-3-3ζ depletion impacted the accessibility of up to 1,244 chromatin regions corresponding in part to adipogenic genes, promoters, and enhancers during the initial stages of adipogenesis. Finally, 14-3-3ζ-regulated chromatin accessibility correlated with the expression of key adipogenic genes. CONCLUSION: Our study establishes 14-3-3ζ as a crucial epigenetic regulator of adipogenesis and highlights the usefulness of deciphering the nuclear 14-3-3ζ interactome to identify novel pro-adipogenic factors and pathways.
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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 | 0.000 | 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) | 0.000 | 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".