FAK regulates IL-33 expression by controlling chromatin accessibility at c-Jun motifs
Billie Georgina Cooper Griffith,
Graeme R. Grimes,
Andrew V. Biankin,
Margaret C Frame
Posted 16 Jul 2020
bioRxiv DOI: 10.1101/2020.07.15.177212
Posted 16 Jul 2020
Focal adhesion kinase (FAK) localises to focal adhesions and is overexpressed in many cancers. FAK can also translocate to the nucleus where it binds to, and regulates, several transcription factors including MBD2, p53 and IL-33 to control gene expression by unknown mechanisms. We have used ATAC-seq to reveal that FAK controls chromatin accessibility at a subset of regulated genes. Integration of ATAC-seq and RNA-seq data showed that FAK-dependent chromatin accessibility is linked to differential gene expression, including of the FAK-regulated cytokine and transcriptional regulator interleukin-33 (Il33), which controls anti-tumour immunity. Analysis of the accessibility peaks on the Il33 gene promoter/enhancer regions revealed sequences for several transcription factors, including ETS and AP-1 motifs, and we show that c-Jun, a component of AP-1, regulates Il33 gene expression by binding to its enhancer in a FAK kinase-dependent manner. This work provides the first demonstration that FAK controls transcription via chromatin accessibility, identifying a novel mechanism by which nuclear FAK regulates biologically-important gene expression.
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