title: SRF Co-factors Control the Balance between Cell Proliferation and Contractility.
abstract: The ERK-regulated ternary complex factors (TCFs) act with the transcription factor serum response factor (SRF) to activate mitogen-induced transcription. However, the extent of their involvement in the immediate-early transcriptional response, and their wider functional significance, has remained unclear. We show that, in MEFs, TCF inactivation significantly inhibits over 60% of TPA-inducible gene transcription and impairs cell proliferation. Using integrated SRF ChIP-seq and Hi-C data, we identified over 700 TCF-dependent SRF direct target genes involved in signaling, transcription, and proliferation. These also include a significant number of cytoskeletal gene targets for the Rho-regulated myocardin-related transcription factor (MRTF) SRF cofactor family. The TCFs act as general antagonists of MRTF-dependent SRF target gene expression, competing directly with the MRTFs for access to SRF. As a result, TCF-deficient MEFs exhibit hypercontractile and pro-invasive behavior. Thus, competition between TCFs and MRTFs for SRF determines the balance between antagonistic proliferative and contractile programs of gene expression.
authors.affiliation: Signalling and Transcription Group, Francis Crick Institute, 1 Midland Rd, London NW1 1AT, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Gualdrini
authors.affiliation: Signalling and Transcription Group, Francis Crick Institute, 1 Midland Rd, London NW1 1AT, UK.
authors.forename: Cyril
authors.initials: C
authors.lastname: Esnault
authors.affiliation: Bioinformatics and Biostatistics STP, Francis Crick Institute, 1 Midland Rd, London NW1 1AT, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Horswell
authors.affiliation: Bioinformatics and Biostatistics STP, Francis Crick Institute, 1 Midland Rd, London NW1 1AT, UK.
authors.forename: Aengus
authors.initials: A
authors.lastname: Stewart
authors.affiliation: Advanced Sequencing STP, Francis Crick Institute, 1 Midland Rd, London NW1 1AT, UK.
authors.forename: Nik
authors.initials: N
authors.lastname: Matthews
authors.affiliation: Signalling and Transcription Group, Francis Crick Institute, 1 Midland Rd, London NW1 1AT, UK. Electronic address: richard.treisman@crick.ac.uk.
authors.forename: Richard
authors.initials: R
authors.lastname: Treisman
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005816:Genetic Complementation Test; D006801:Humans; D051379:Mice; D026362:Serum Response Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D050801:Ternary Complex Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C494112:ELK1 protein, human; C511173:Mrtfa protein, mouse; D026362:Serum Response Factor; D050801:Ternary Complex Factors; D015534:Trans-Activators; D050807:ets-Domain Protein Elk-1; D048049:Extracellular Signal-Regulated MAP Kinases; D013755:Tetradecanoylphorbol Acetate
keywords: Elk-1; Hi-C; Ras/MAPK signaling; SRF; Ternary Complex Factor; cell contraction; cell proliferation; immediate-early genes; transcription; transcription factors