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SRF Co-factors Control the Balance between Cell Proliferation and Contractility

Francesco Gualdrini1, Cyril Esnault1, Stuart Horswell2

  • 1Signalling and Transcription Group, Francis Crick Institute, 1 Midland Rd, London NW1 1AT, UK.

Molecular Cell
|November 22, 2016
PubMed

Insights

Ternary complex factors (TCFs) and serum response factor (SRF) control gene transcription. TCFs antagonize myocardin-related transcription factors (MRTFs), balancing cell proliferation and contraction.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Gene Regulation

Background:

  • Ternary complex factors (TCFs) partner with serum response factor (SRF) to drive gene transcription in response to mitogens.
  • The precise role and broader functional impact of TCFs in immediate-early gene responses remain incompletely understood.

Purpose of the Study:

  • To elucidate the functional significance of TCFs in regulating gene transcription and cell proliferation.
  • To investigate the interplay between TCFs, SRF, and MRTFs in controlling gene expression programs.

Main Methods:

  • CRISPR-Cas9 mediated TCF inactivation in mouse embryonic fibroblasts (MEFs).
  • Chromatin immunoprecipitation sequencing (ChIP-seq) for SRF.
  • Hi-C for genome-wide interaction analysis.
  • Analysis of TPA-inducible gene transcription and cell proliferation.

Main Results:

  • TCF inactivation inhibited over 60% of TPA-inducible genes and impaired MEF proliferation.
  • Over 700 direct SRF target genes were identified as TCF-dependent, involved in signaling, transcription, and proliferation.
  • TCFs antagonize MRTF-mediated SRF target gene expression by competing for SRF binding.
  • TCF-deficient MEFs displayed hypercontractile and pro-invasive phenotypes.

Conclusions:

  • Competition between TCFs and MRTFs for SRF binding is a critical determinant of gene expression.
  • This competition balances opposing cellular programs, including proliferation and cytoskeletal contractility.
  • TCFs play a vital role in regulating gene transcription, cell proliferation, and cellular behavior.
Keywords:
Elk-1Hi-CRas/MAPK signalingSRFTernary Complex Factorcell contractioncell proliferationimmediate-early genestranscriptiontranscription factors

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