Alternative splicing and nonsense-mediated mRNA decay regulate gene expression of serum response factor

Serum response factor (SRF) is an important transcription factor that regulates a variety of genes in many tissues during development, maturation and aging. The SRF protein also controls the expression of SRF target genes, including the SRF gene itself. However, it is incompletely established how SRF isoforms contribute to the regulation of SRF gene expression. In the present study, we report the identification of three novel SRF isoforms in human tissue. We found that one novel isoform, SRF-▵3, contained a premature termination codon (PTC), which was a target of nonsense-mediated mRNA decay (NMD). By contrast, the SRF-▵345 isoform protein was able to specifically bind to the serum response element, and to repress the SRF gene promoter activity. Therefore, we propose that SRF isoforms regulate expression of the SRF gene via two different mechanisms. One mechanism is to reduce the abundance of SRF transcripts via coupled alternative splicing and NMD, the other one is to regulate the SRF gene expression via a feedback mechanism in which the SRF isoform proteins bind to the SRF gene promoter region. Analysis of hundreds of SRF cDNA clones derived from human hearts of fetuses, young adults, old and very old individuals revealed that SRF isoform transcripts were increased in the human heart with advancing age. Our data indicate that the SRF isoforms were differentially expressed in the human versus mouse cardiac muscle. Alternative splicing and NMD likely maintain a delicate balance of SRF transcripts and/or proteins among the full-length SRF form and various SRF isoforms that are critical to the regulation of many SRF target genes, including the SRF gene itself.