Proteomic analysis of SRF associated transcription complexes identified TFII-I as modulator of SRF function in neurons

Abstract

The serum response factor (SRF) is a neuronal activity regulated transcription factor (TF) mediating an immediate early (IEGs, e.g. cFos, Egr1) and actin cytoskeletal gene response. SRF activity is adjusted by two competing cofactor families, ternary complex factors (TCF; e.g. Elk-1) and myocardin related transcription factors (MRTF).We investigated mechanisms of SRF activation upon seizure associated neuronal activity in mice. SRF serine 103 phosphorylation or promoter binding was not obviously changed upon neuronal activation. In contrast, a SRF directed proteomic analysis uncovered established and potentially novel components of SRF associated protein complexes whose abundance was modified by neuronal activity. This included the general transcription factor TFII-I for which we provide a first functional analysis in neurons. TFII-I modulated neuronal SRF target gene expression, enhanced nerve fiber growth and modulated the shape of neuronal growth cones. Interestingly, TFII-I modulated two SRF cofactors, Elk-1 and MRTF-A, in opposite directions. TFII-I and Elk-1 co-expression enhanced SRF target gene abundance, SRF promoter binding and neurite growth, whereas TFII-I and MRTF-A resulted in opposite outcomes.In summary, we provide a first proteome wide analysis of SRF associated proteins. We characterized TFII-I as modulator of SRF activity by imposing differential impact on two SRF cofactors.