摘要：SummaryKrüppel-like factor 4 (KLF4) is a transcription factor that has been proven necessary for both induction and maintenance of pluripotency and self-renewal. Whole-genome sequencing defined a unique mutation in KLF4 (KLF4K409Q) in human meningiomas. However, the molecular mechanism of this tumor-specific KLF4 mutation is unknown. Using genome-wide high-throughput and focused quantitative transcriptional approaches in human cell lines, primary meningeal cells, and meningioma tumor tissue, we found that a change in the evolutionarily conserved DNA-binding domain of KLF4 alters its DNA recognition preference, resulting in a shift in downstream transcriptional activity. In the KLF4K409Q-specific targets, the normally silent fibroblast growth factor 3 (FGF3) is activated. We demonstrated a neomorphic function of KLF4K409Qin stimulatingFGF3transcription through binding to its promoter and in using short tandem repeats (STRs) located within the locus as enhancers.Graphical abstractDisplay OmittedHighlights•∼15% of meningioma patients share a unique missense mutation K409Q in KLF4•K409Q mutation occurs in DNA-binding domain and leads to altered DNA specificity•KLF4K409Qbinds to STRs in theFGF3gene locus and activatesFGF3transcription•FGF3 may contribute to aberrant cell proliferation and meningioma growthMolecular biology; Cancer; Transcriptomics.
