Venkatasubramanian, A.; Thakkar, C.; Yang, Z.; Ivessa, A.; Sayed, N.; Abdellatif, M.; Sayed, D.

Klf9 is a cardiac-enriched transcription factor of the Kruppel-like factor (Klf) family. Klf9 levels decrease during cardiac hypertrophy; however, no studies have examined its transcriptional targets or role in the progression of hypertrophy. Here, we report genome-wide differential Klf9 occupancy during cardiac hypertrophy, with a predominant enrichment at the promoters of metabolic genes. Further, using conditional Klf9 knock-in mice subjected to pressure overload for 1 or 2 weeks, we show that restoring Klf9 expression initially inhibits hypertrophy but later leads to early-onset heart failure. We conclude that a decrease in Klf9 is required for metabolic adaptations that support the development of compensatory hypertrophy.