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SRF co-factors control the balance between cell proliferation and contractility
journal contributionposted on 2020-08-05, 16:50 authored by Francesco Gualdrini, Cyril Esnault, Stuart Horswell, Aengus Stewart, Nik Matthews, Richard Treisman
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.
Elk-1Hi-CRas/MAPK signalingSRFTernary Complex Factorcell contractioncell proliferationimmediate-early genestranscriptiontranscription factorsAnimalsBase SequenceCell LineCell ProliferationExtracellular Signal-Regulated MAP KinasesFibroblastsGene Expression ProfilingGene Expression RegulationGenetic Complementation TestHumansMiceSerum Response FactorSignal TransductionTernary Complex FactorsTetradecanoylphorbol AcetateTrans-ActivatorsTranscription, Geneticets-Domain Protein Elk-1Treisman FC001190ASCBHTS-ack06 Biological Sciences11 Medical and Health SciencesDevelopmental Biology