Mar 21, 2020

The pathognomonic FOXL2 C134W mutation alters DNA binding specificity

bioRxiv
Annaick CarlesMartin Hirst

Abstract

The somatic missense point mutation c.402C>G (p.C134W) in the FOXL2 transcription factor is pathognomonic for adult-type granulosa cell tumours (AGCT) and a diagnostic marker for this tumour type. However, the molecular consequences of this mutation and its contribution to the mechanisms of AGCT pathogenesis remain unclear. To explore the mechanisms driving FOXL2C134W pathogenicity we engineered V5-FOXL2WT and V5-FOXL2C134W inducible isogenic cell lines and performed ChIP-seq and transcriptome profiling. We found that FOXL2C134W associates with the majority of the FOXL2 WT DNA elements as well as a large collection of unique elements genome-wide. We confirmed an altered DNA binding specificity for FOXL2C134W in vitro and identified unique targets of FOXL2C134W including SLC35F2 whose expression increased sensitivity to YM155 in our model.

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Mentioned in this Paper

Tumor Staging Descriptor P
Gene Expression Profiling
Granulosa Cell Tumor
Protein Expression
DNA Binding
Forkhead Box Protein L2
Altretamine/Cisplatin/Cyclophosphamide/Misonidazole Protocol
SLC35F2 protein, human
Vanadium 5+
Survivin inhibitor YM155

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