Supervisors: Prof. Dr. Guido Posern
(1) The regulation of MRTF-A and its target genes by microRNAs
(2) Understanding the miRNA-MRTF circuitry in muscle cell differentiation
Background and significance
The development and differentiation of muscle cells is a tightly regulated process including several signaling pathways, transcription factors and post-transcriptional processes. However, the details of the circuitries which govern the differentiation into a specific muscle subtype are not well understood, despite their significance in e.g. artheriosclerotic lesion formation and muscle regeneration.
The myocardin family of transcription factors plays an essential role for differentiation and function of both, skeletal and smooth muscle cells. They are coactivators of the Serum Response Factor (SRF) and control several muscle-specific genes, including skeletal muscle alpha-actin (acta1; SMA), smooth muscle alpha-actin (acta2; SkMA), myosin heavy chain and SM22 . Whereas Myocardin expression is specific to smooth and cardiac muscle, the Myocardin-related transcription factors A (MRTF-A; syn. MAL, MKL1) and MRTF-B are widely expressed. MRTFs, but not myocardin, connect Rho family GTPases and actin dynamics with SRF-mediated transcription. MRTFs are also implicated in the development of myoepithelial cells, myofibroblast differentiation and fibrosis, cell motility and tumor metastasis. However, the regulation of MRTF expression itself is unknown.
Several miRNAs are specifically expressed in differentiating muscle cells, where they post-transcriptionally regulate gene expression and are required for the contractile phenotype. A prominent example is the miR-1, which is transcriptionally regulated by myocardin and in a negative feedback loop dampens the expression of contractile proteins in smooth muscle cells. MiR-206 is also predominantly expressed in muscle. How these miRs affect MRTF-A dependent differentiation of smooth or skeletal muscle cells remains largely elusive.