Glucocorticoid-Responsive Transcription Factor Krüppel-Like Factor 9 Regulates fkbp5 and Metabolism

Abstract

Krüppel-like factor 9 (Klf9) is a feedforward regulator of glucocorticoid receptor (GR) signaling. Here we show that in zebrafish <i>klf9</i> is expressed with GR-dependent oscillatory dynamics in synchrony with <i>fkbp5</i>, a GR target that encodes a negative feedback regulator of GR signaling. We found that <i>fkbp5</i> transcript levels are elevated in <i>klf9</i> ^-/- mutants and that Klf9 associates with chromatin at the <i>fkbp5</i> promoter, which becomes hyperacetylated in <i>klf9</i> ^-/ <i>^-</i> mutants, suggesting that the GR regulates <i>fkbp5</i> via an incoherent feedforward loop with <i>klf9</i>. As both the GR and Fkbp5 are known to regulate metabolism, we asked how loss of Klf9 affects metabolic rate and gene expression. We found that <i>klf9</i> ^-/- mutants have a decreased oxygen consumption rate (OCR) and upregulate glycolytic genes, the promoter regions of which are enriched for potential Klf9 binding motifs. Our results suggest that Klf9 functions downstream of the GR to regulate cellular glucocorticoid responsivity and metabolic homeostasis.