MRTFA^OEleads to retention of SRF binding at CArG sites. Metaprofiles of binding sites for all treatment groups for peaks that increase (A; 211 peaks) or decrease (B; 278 peaks) when HEL cells are treated with TPA. Reads were normalized to per kilobase per million mapped reads. Average intensity of SRF binding was calculated from the center of each peak in a ±1500-bp window. Visually, the confidence interval is represented by a ribbon, which includes 95% of the sampled values. In both panels A and B, SRF binding in the MRTFA^OETPA⁺ group is higher than in the TPA⁺ group, suggesting increased SRF binding to chromatin in the presence of excess MRTFA. *P ≤ 10⁻⁸ vs TPA⁺. (C) Schematic representing the current understanding of the SRF/MRTFA regulatory axis based on studies in fibroblasts. MRTFA dimers bind to SRF dimers, which are positioned at a CArG site in the serum response element, to activate expression of downstream genes. (D) In the SRF/TCF regulatory axis, TCF binds to SRF dimers positioned at a CArG site as well as an upstream ETS motif to activate gene expression. (E-F) CArG and ETS motifs used to query SRF binding sites with HOMER (hypergeometric optimization of motif enrichment). (G) Percentages of SRF binding sites in HEL cells with CArG motifs or cooccurring CArG and ETS motifs that either increase or decrease between 3 different comparison groups. MRTFA^OE augments SRF recruitment and abrogates loss of SRF from CArG motifs.