Mutated KLF4(K409Q) in meningioma binds STRs and activates FGF3 gene expression

Krüppel-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 KLF4K409Q in stimulating FGF3 transcription through binding to its promoter and in using short tandem repeats (STRs) located within the locus as enhancers. [Display omitted] •∼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•KLF4K409Q binds to STRs in the FGF3 gene locus and activates FGF3 transcription•FGF3 may contribute to aberrant cell proliferation and meningioma growth Molecular biology; Cancer; Transcriptomics.