title: Genomic analysis of the role of transcription factor C/EBPδ in the regulation of cell behaviour on nanometric grooves.
abstract: 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.
authors.affiliation: Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Wiejak
authors.forename: Penelope M
authors.initials: PM
authors.lastname: Tsimbouri
authors.forename: Pawel
authors.initials: P
authors.lastname: Herzyk
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Dalby
authors.forename: Graham
authors.initials: G
authors.lastname: Hamilton
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Yarwood
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D048430:Cell Shape / Q000235:genetics; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D016384:Consensus Sequence / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D016678:Genome / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D049329:Nanostructures / Q000737:chemistry*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051743:CCAAT-Enhancer-Binding Protein-delta