Abstract
SummaryThe 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.
Highlights
Ras-ERK signaling is critical for control of proliferation, invasion, and metastasis
In mouse embryonic fibroblasts (MEFs), ternary complex factors (TCFs) inactivation significantly inhibits over 60% of tetradecanoyl phorbol-13-acetate (TPA)-inducible gene transcription and impairs cell proliferation
Using integrated serum response factor (SRF) chromatin immunoprecipitation (ChIP)-seq and Hi-C data, we identified over 700 TCF-dependent SRF direct target genes involved in signaling, transcription, and proliferation
Summary
Ras-ERK signaling is critical for control of proliferation, invasion, and metastasis. Many IE genes are controlled by the transcription factor serum response factor (SRF, Srf), which is required for Ras-induced cell-cycle re-entry but not for proliferation per se (Gauthier-Rouviere et al, 1990; Schratt et al, 2001). The three ternary complex factors (TCFs) Elk-1, Net, and SAP-1 (Elk, Elk, and Elk4) are Ets domain proteins, regulated by Ras-ERK signaling (Buchwalter et al, 2004; Shaw et al, 1989), whereas the myocardin-related transcription factors (MRTFs) Mkl and Mkl respond to the Rho-actin pathway (Miralles et al, 2003; Olson and Nordheim, 2010). Some IE genes appear to be coupled to one pathway or the other, but in smooth muscle cells, platelet-derived growth factor (PDGF) can induce cofactor exchange (Wang et al, 2004)
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