Mechanisms of Glucocorticoid‐mediated Induction of Krüppel‐Like Factor 9 in the Human Airways
Notice bibliographique
Résumé
RATIONALE Glucocorticoids (GCs) are stress hormones that act on the GC receptor (GR; NR3C1) to elicit effects, including repression of inflammatory gene expression. However, the molecular mechanisms for this repressive effect remain unclear. Since GC, as inhaled corticosteroids, are the cornerstone of asthma treatment, a comparative transcriptome analysis of human airway epithelial cell variants was performed following GC treatment. This revealed 17 genes that were induced in common by GC. Of these, 7 genes were associated with gene ontology terms for transcriptional regulation. Many of these genes, including KLF9, were also induced by inhaled GC in vivo in the human airways. While, KLF9 is a probable repressor of transcription and has been implicated in cellular proliferation and differentiation, little is known about the GC‐mediated regulation of KLF9 in the airways. The current work addresses this knowledge gap. RESULTS GC‐mediated induction of KLF9 mRNA was confirmed in the airway epithelial cell lines, pulmonary type II A549 and bronchial epithelial BEAS‐2B cells, as well as in different primary cell types, including bronchial epithelial (HBE), vascular endothelial, fibroblast, and smooth muscle (ASM) cells, that are all present in the airways. Additionally, multiple GCs, including hydrocortisone, dexamethasone, and budesonide all induced KLF9 to a similar extent in A549 cells. This induction was abolished in A549 cells either by pretreating cells with the GR antagonist, Org34517, or by knocking down GR with siRNA. Chromatin immunoprecipitation of GR following glucocorticoid treatment in A549 and BEAS‐2B cells showed GR binding to sites 5.9, 6.7, 25, and 65 kb upstream of the KLF9 gene. Public domain data suggests that these sites may all possess enhancer activity and eRNA (enhancer RNA) expression was induced following GC treatment. Cellular fractionation showed that both basal and GC‐induced KLF9 protein was exclusively nuclear. CONCLUSIONS The current work confirms that KLF9 is GC‐induced in multiple structural cell types (epithelial, fibroblast, airway smooth muscle and endothelial) that are found in the airways. In A549 cells the GC‐mediated induction of KLF9 was GR‐dependent. Since GR bound to, and appeared to activate, multiple enhancers upstream of the KLF9 gene, direct transactivation by GR is likely. GC induction of KLF9 therefore represents a highly conserved transactivation event that can be used to model transcriptional control by GR. Further deciphering the molecular events that occur at the KLF9 upstream promotor following GC treatment will enhance our understanding of how GR drives gene expression. Support or Funding Information This work was supported by: RN grants: Canadian Institutes of Health Research (CIHR), and Natural Sciences and Engineering Research Council of Canada (NSERC) discovery grant; MMM studentships: NSERC Postgraduate Scholarship – Doctoral, Queen Elizabeth II Doctoral scholarship, and The Lung Association – Alberta & NWT studentship award. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».