Research from the Epigenomics Program was recently published, in coordination with the Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Physiology and Biophysics, and Medicine, focusing on the KLF14 gene, which has elicited attention as master regulator of lipid metabolism.
Sphingosine kinase 1 (SK1) is an FGF-inducible gene responsible for generation of sphingosine-1-phosphate, a critical lipid signaling molecule implicated in diverse endothelial cell (EC) functions. In this study, we identified SK1 as a target of the canonical fiborblast growth factor 2 (FGF2)/fibroblast growth factor receptor 1 (FGFR1) activation pathway in EC and sought to identify novel transcriptional pathways that mediate lipid signaling.
Studies using the 1.9-Kb SK1 promoter and deletion mutants revealed that basal and FGF2–stimulated promoter activity occurred through two GC-rich regions located within 633-bp of the transcription start site. Screening for GC-rich binding transcription factors that could activate this site demonstrated that KLF14, a gene implicated in obesity and the metabolic syndrome, binds to this region. Congruently, overexpression of KLF14 increased basal and FGF2 stimulated SK1 promoter activity by 3-fold, and this effect was abrogated after mutation of the GC-rich sites.
KLF14 acts as a transcriptional activator for the generation of lipid signaling molecules.
In addition, KLF14 siRNA transfection decreased SK1 mRNA and protein levels by 3-fold. Congruently, SK1 mRNA and protein levels were decreased in livers from KLF14 knockout mice. Combined, luciferase, gel-shift, and chromatin immunoprecipitation assays showed that KLF14 couples to p300 to increase the levels of histone marks associated with transcriptional activation (H4K8ac, and H3K14ac), while decreasing repressive marks (H3K9me3 and H3K27me3). Collectively, the results demonstrate a novel mechanism whereby SK1 lipid signaling is regulated by epigenetic modifications conferred by KLF14 and p300.
Thus, this is the first description of the activity and mechanisms underlying the function of KLF14 as an activator protein and novel regulator of lipid signaling.
KLF14 has recently elicited significant attention since extensive genetic studies in humans have identified a central role of this protein in the development of metabolic diseases, in particular those that regulate lipid metabolism. In fact, due to its contribution to metabolic diseases, KLF14 has been recently referred to as a “conductor of the metabolic syndrome orchestra” (28). However, in spite of its importance, little is known about the mechanisms by which KLF14 regulates lipid biology at the molecular and cellular levels.
The current study significantly advances this field of research by providing novel insights into the role of KLF14 in the transcriptional regulation of lipid signaling, as well as outlining a novel FGF2-FGFR1-KLF14-p300-SK1-S1P pathway. These findings are of relevance to the areas of KLF proteins, growth factor signaling, and lipid-mediated signaling in normal biology and have the potential to contribute to a better understanding of diseases that associate with alterations in KLF14.
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