Abstract
The transcription factor SRF (serum response factor) recruits two families of coactivators, the MRTFs (myocardin-related transcription factors) and the TCFs (ternary complex factors), to couple gene transcription to growth factor signaling. Here we investigated the role of the SRF network in the immediate transcriptional response of fibroblasts to serum stimulation. SRF recruited its cofactors in a gene-specific manner, and virtually all MRTF binding was directed by SRF. Much of SRF DNA binding was serum-inducible, reflecting a requirement for MRTF-SRF complex formation in nucleosome displacement. We identified 960 serum-responsive SRF target genes, which were mostly MRTF-controlled, as assessed by MRTF chromatin immunoprecipitation (ChIP) combined with deep sequencing (ChIP-seq) and/or sensitivity to MRTF-linked signals. MRTF activation facilitates RNA polymerase II (Pol II) recruitment or promoter escape according to gene context. MRTF targets encode regulators of the cytoskeleton, transcription, and cell growth, underpinning the role of SRF in cytoskeletal dynamics and mechanosensing. Finally, we show that specific activation of either MRTFs or TCFs can reset the circadian clock.
Highlights
The serum response factor (SRF) transcription factor is an important regulator of cytoskeletal and muscle-specific gene expression
We showed that Rho-actin signaling to the MRTF family of SRF coactivators regulates multiple aspects of the transcriptional response to serum stimulation in fibroblasts
SRF appears to be the primary targeting agent for the MRTFs in fibroblasts: Ninety-five percent of 2416 MRTF-binding events detected in fibroblasts were SRF-associated, and we found no evidence for MRTF recruitment by other sequence-specific DNA-binding proteins as proposed by others (Qiu et al 2005; Morita et al 2007)
Summary
The SRF (serum response factor) transcription factor is an important regulator of cytoskeletal and muscle-specific gene expression (for reviews, see Posern and Treisman 2006; Olson and Nordheim 2010). SRF was first identified in studies of the fibroblast serum response, a classical model for cell cycle re-entry and wound healing It functions in partnership with members of two families of signal-regulated cofactors: the MRTFs (myocardin-related transcription factors; MRTF-A, MRTF-B, and myocardin itself) and the TCF (ternary complex factor) family of Ets domain proteins (SAP-1, Elk-1, and Net). Functional studies suggest that TCF and MRTF binding is gene-specific (Gineitis and Treisman 2001; Miralles et al 2003; Wang et al 2004), but the generality of this and its molecular basis remain to be determined. Our data suggest that MRTF– SRF signaling is central to the serum response and strongly support the emerging idea that SRF signaling underlies the response of cells to mechanical cues
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