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

Alla V Tsytsykova; Graham Wiley; Chuang Li; Richard C Pelikan; Lori Garman; Francis A Acquah; Blaine H M Mooers; Erdyni N Tsitsikov; Ian F Dunn

doi:10.1016/j.isci.2022.104839

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

iScience. 2022 Aug 3;25(8):104839. doi: 10.1016/j.isci.2022.104839. eCollection 2022 Aug 19.

Authors

Alla V Tsytsykova¹, Graham Wiley², Chuang Li³, Richard C Pelikan³, Lori Garman³, Francis A Acquah⁴, Blaine H M Mooers^{5

4}, Erdyni N Tsitsikov¹, Ian F Dunn¹

Affiliations

¹ Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
² Clinical Genomics Center, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
³ Oklahoma Medical Research Foundation, Genes & Human Disease Research Program, Oklahoma City, OK 73104, USA.
⁴ Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
⁵ Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

Abstract

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 (KLF4^K409Q) 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 KLF4^K409Q-specific targets, the normally silent fibroblast growth factor 3 (FGF3) is activated. We demonstrated a neomorphic function of KLF4^K409Q in stimulating FGF3 transcription through binding to its promoter and in using short tandem repeats (STRs) located within the locus as enhancers.

Keywords: Cancer; Molecular biology; Transcriptomics.

Abstract

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