Gαq-stimulated gene expression is insensitive to Bromo extra terminal domain inhibitors in HEK 293 cells
Bibliographic record
Abstract
Abstract Bromodomain and extraterminal domain (BET) family proteins are ubiquitous transcriptional co-activators that function broadly in gene expression programs associated with cellular differentiation, proliferation, and stress responses. Pharmacological inhibition of BET proteins with small molecules that disrupt bromodomain engagement with acetyllysine residues (such as JQ1), or that drive their degradation through the ubiquitin-proteasome system (such as dBET6), ameliorates pathological gene expression in a range of systems and shows promise as a potential therapeutic strategy. BET involvement in gene expression responses is not universal, and understanding of the cell-type and signaling pathway requirements that dictate BET dependence remains incomplete. We previously demonstrated that, in neonatal rat cardiomyocytes, GPCR-induced hypertrophy response depended strongly on the BET protein Brd4 when signaling was coupled to Gαs, but not Gαq. Here we tested whether Brd4 was differentially responsive to G protein isoforms in HEK 293 cells by expressing Gαs or Gαq-coupled D esigner R eceptors E xclusively A ctivated by D esigner D rugs (DREADDs). Gαq induced expression of a group of early response genes and inflammatory genes in a manner largely insensitive to pharmacological BET inhibition, consistent with our previous data in cardiomyocytes. Gαs activated a small subset of the Gαq-induced genes, but this effect was largely reversed by the BET degrader molecule dBET6. Our data further suggest that there may be general signaling requirements to activate Brd4 across cell types. Highlights - We tested whether Bromodomain and extraterminal domain (BET) family proteins were differentially responsive to G protein isoforms in HEK 293 cells by expressing Gαs or Gαq-coupled D esigner R eceptors E xclusively A ctivated by D esigner D rugs (DREADDs). - Gαq induced expression of a group of genes but was largely insensitive to pharmacological BET inhibition, consistent with our previous data in cardiomyocytes. - Gαs activated a small subset of the Gαq-induced genes, but was sensitive to the BET degrader molecule dBET6. - Distinct G protein-dependent effects may be conserved across cell types.
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| 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) | 0.002 | 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".