Mendaley data for "Phase separation mediated transcriptional activity of FOXK1 triggers glycolysis and facilitates renal fibrosis"

Description

Metabolic reprogram featured with enhanced glycolysis in tubular cells facilitates the renal fibrosis, but the mechanism underlying this dysregulation remain elusive. Forkhead box protein K1 (FOXK1), serving as a transcriptional factor involved in the regulation of cell energy metabolism, was recently reported by us a core regulator on EMT process in the context of kidney fibrosis. It arose the speculation that FOXK1 participates in reshaping the metabolic landscape of TECs along with kidney fibrosis progression. In this study, an expression pattern of fibrosis associated FOXK1 induction and upregulation in TECs was observed in fibrotic kidneys from either CKD patients or animal model. Meanwhile, pro-fibrotic stimulus triggered FOXK1 expression and nuclear translocation in cultured HK-2 cells. Genetic modification of FOXK1 expression in TECs in vivo or in vitro resulted in remarkable alteration of glycolytic metabolism and fibrotic effects. A set of glycolysis-related genes, including Ldha, were then identified as the direct targets of FOXK1 in the TECs by chromatin immunoprecipitation analysis. Mechanistically, Nuclear translocated FOXK1 bound to the target motif of the glycolysis-related genes to promote transcription through a mechanism of liquid-liquid phase separation. The core intrinsically disordered regions (IDRs) of FOXK1 responsible for phase separation formation were identified. We also found that RNA Pol II was incorporated into the condensates initiated by FOXK1 to spark the target gene transcription. Collectively, our findings revealed a novel role of FOXK1 in driving kidney fibrosis through bolstering glycolysis transition in tubular cells and shed light in exploring potential therapeutic target for renal fibrosis.

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