Genomic analysis of the role of transcription factor C/EBPδ in the regulation of cell behaviour on nanometric grooves

Wiejak, J., Tsimbouri, P. M. , Herzyk, P. , Dalby, M. J. , Hamilton, G. and Yarwood, S. J. (2013) Genomic analysis of the role of transcription factor C/EBPδ in the regulation of cell behaviour on nanometric grooves. Biomaterials, 34(8), pp. 1967-1979. (doi: 10.1016/j.biomaterials.2012.11.036) (PMID:23245923) (PMCID:PMC3543902)

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C/EBPδ is a tumour suppressor transcription factor that induces gene expression involved in suppressing cell migration. Here we investigate whether C/EBPδ-dependent gene expression also affects cell responses to nanometric topology. We found that ablation of the C/EBPδ gene in mouse embryonal fibroblasts (MEFs) decreased cell size, adhesion and cytoskeleton spreading on 240 nm and 540 nm nanometric grooves. ChIP-SEQ and cDNA microarray analyses demonstrated that many binding sites for C/EBPδ, and the closely related C/EBPβ, exist throughout the mouse genome and control the upregulation or downregulation of many adjacent genes. We also identified a group of C/EBPδ-dependent, trans-regulated genes, whose promoters contained no C/EBPδ binding sites and yet their activity was regulated in a C/EBPδ-dependent manner. These genes include signalling molecules (e.g. SOCS3), cytoskeletal components (Tubb2, Krt16 and Krt20) and cytoskeletal regulators (ArhGEF33 and Rnd3) and are possibly regulated by cis-regulated diffusible mediators, such as IL6. Of particular note, SOCS3 was shown to be absolutely required for efficient cell spreading and contact guidance on 240 nm and 540 nm nanometric grooves. C/EBPδ is therefore involved in the complex regulation of multiple genes, including cytoskeletal components and signalling mediators, which influence the nature of cell interactions with nanometric topology.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Tsimbouri, Dr Monica and Yarwood, Dr Stephen and Dalby, Professor Matthew and Hamilton, Dr Graham and Herzyk, Dr Pawel and Wiejak, Dr Jolanta
Authors: Wiejak, J., Tsimbouri, P. M., Herzyk, P., Dalby, M. J., Hamilton, G., and Yarwood, S. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Biomaterials
ISSN (Online):1878-5905
Published Online:13 December 2012
Copyright Holders:Copyright © 2012 Elsevier Ltd.
First Published:First published in Biomaterials 34(8):1967-1979
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
528251The Role of EPAC1-regulated Protein Kinase C Isoforms in Mediating C/EBPdelta -dependent, Anti-inflammatory Actions of Cyclic AMP in Vascular Endothelial CellsStephen YarwoodBritish Heart Foundation (BHF)PG/10/026/28303RI MOLECULAR CELL & SYSTEMS BIOLOGY
498581EPAC1 and ERK-dependent activation of C/EBP transcription factors: a new cyclic AMP-activated anti-inflammatory gene expression module in vascular endothelial cellsTimothy PalmerBritish Heart Foundation (BHF)PG/08/125/26415RI CARDIOVASCULAR & MEDICAL SCIENCES
593571Manipulation of cancer cells by nanotopography: strategies to control migration, proliferation and apoptosis (ISSF Catalyst Fund)Penelope TsimbouriWellcome Trust (WELLCOME)097821/Z/11/ZRI MOLECULAR CELL & SYSTEMS BIOLOGY