FAK regulates IL-33 expression by controlling chromatin accessibility at c-Jun motifs

Griffith, B. G.C., Upstill-Goddard, R., Brunton, H., Grimes, G. R., Biankin, A. , Serrels, B., Byron, A. and Frame, M. C. (2021) FAK regulates IL-33 expression by controlling chromatin accessibility at c-Jun motifs. Scientific Reports, 11, 229. (doi: 10.1038/s41598-020-80111-9) (PMID:33420223) (PMCID:PMC7794255)

Abstract

Focal adhesion kinase (FAK) localizes 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-tumor 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.

• Item Type: Articles
• Additional Information: The work was funded by Cancer Research UK (grants C157/A15703 and C157/A24837 to M.C.F.).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Serrels, Dr Bryan and Biankin, Professor Andrew and Upstill-Goddard, Dr Rosie
• Authors: Griffith, B. G.C., Upstill-Goddard, R., Brunton, H., Grimes, G. R., Biankin, A., Serrels, B., Byron, A., and Frame, M. C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Scientific Reports
• Publisher: Nature Research
• ISSN: 2045-2322
• ISSN (Online): 2045-2322
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Scientific Reports 11:229
• Publisher Policy: Reproduced under a Creative Commons License