Effect of cell history on response to helix–loop–helix family of myogenic regulators

Abstract

In multinucleated heterokaryons formed from the fusion of differentiated muscle cells to either hepatocytes or fibroblasts, muscle-specific gene expression is activated, liver-specific gene expression is repressed, and there are changes in the location of the Golgi apparatus. An understanding of the regulatory mechanisms that underlie this plasticity is of particular interest given the stability of the differentiated state in vivo. We have now investigated whether MyoD or myogenin, regulators of muscle-specific gene expression that have a helix-loop-helix motif, can induce the phenotypic conversion observed in heterokaryons. When these regulators were stably or transiently introduced into fibroblasts or hepatocytes by microinjection, transfection or retroviral infection with complementary DNA in expression vectors, fibroblasts expressed muscle-specific genes, whereas hepatocytes did not. However, fusion of hepatocytes stably expressing MyoD to fibroblasts resulted in activation in the heterokaryon of muscle-specific genes of both cell types. These results imply that other regulators, present in fibroblasts but not in hepatocytes, are necessary for the activation of muscle-specific genes, and indicate that the differentiated state of a cell is dictated by its history and a dynamic interaction among the proteins that it contains.

Transformation-defective v-ski induces MyoD and myogenin expression but not myotube formation.

“…Although members of the MyoD family convert a variety of cell types to the myogenic lineage (28), their activity is not always sufficient for myogenic conversion in cells of nonmesodermal origin (26). Our results show that even in QECs, which have demonstrated myogenic potential, transcriptional activation of both MyoD and myogenin is not sufficient to lead to fusion and a complete muscle phenotype.…”

Pioneer transcription factors in cell reprogramming

“…However, exogenous MyoD in endodermal and ectodermal cells failed to induce a full phenotypic switch (Weintraub et al 1989;Sch€ afer et al 1990). Later studies revealed that MyoD induces myogenin through cooperation with the Pbx factor, which is constitutively bound to MyoD target sites in fibroblasts prior to MyoD expression (Berkes et al 2004).…”

Epidermal differentiation: the bare essentials.

“…Expression of Myo D in certain fibroblast cell lines in vitro appears to be sufficient to convert them into myoblasts (Lassar et al, 1986). While the Myo D family plays a central role in myoblast differentiation, regulation of these regulators involves a complex program of transcriptional and posttranslational controls, and moreover, there may be more to muscle differentiation than Myo D and its family (see for example Schafer et al, 1990). Hence for muscle, at least one family of central regulators controlling the balance of growth and differentiation are transcription factors, which are controlled by a dynamic group of intracellular and extracellular regulators.…”