The epigenetic network regulating muscle development and regeneration

Abstract

This review focuses on our current knowledge of the epigenetic changes regulating gene expression at the chromatin and DNA level, independently on the primary DNA sequence, to reprogram the nuclei of muscle precursors during developmental myogenesis and muscle regeneration. These epigenetic marks provide the blueprint by which the extra-cellular cues are interpreted at the nuclear level by the transcription machinery to select the repertoire of tissue-specific genes to be expressed. The reversibility of some of these changes necessarily reflects the dynamic nature of skeletal myogenesis, which entails the progression through two antagonistic processes-proliferation and differentiation. Other epigenetic modifications are instead associated to events conventionally considered as irreversible-e.g. maintenance of lineage commitment and terminal differentiation. However, recent results support the possibility that these events can be reversed, at least upon certain experimental conditions, thereby revealing a dynamic nature of many of the epigenetic modifications underlying skeletal myogenesis. The elucidation of the epigenetic network that regulates transcription during developmental myogenesis and muscle regeneration might provide the information instrumental to devise pharmacological interventions toward selective manipulation of gene expression to promote regeneration of skeletal muscles and possibly other tissue.

RAGE Expression in Rhabdomyosarcoma Cells Results in Myogenic Differentiation and Reduced Proliferation, Migration, Invasiveness, and Tumor Growth

“…Data obtained with SB203580 were in line with data in Figure 3A and with the notion that p38 MAPK needs to be activated for myoblasts to differentiate 15,17,18 and indicated that expression of RAGE in TE671 cells was sufficient to restore a crucial event in myogenic differentiation, ie, sustained p38 MAPK activation. By contrast, inhibition of mitogenactivated protein kinase kinase-ERK1/2 favored the execution of the myogenic program activated by RAGE engagement in TE671/RAGE cells ( Figure 3E) in accordance with the notion that ERK1/2 inactivation results in enhanced myoblast differentiation.…”

“…We found that TE671 cells do not express RAGE, myogenin, or MHC; proliferate at a high rate; and are unable to complete the myoblast differentiation pro- p38 MAPK activity is crucial for activation of the myogenic program in myoblasts and RMS cells, and Akt is also required for myoblast differentiation and myoblast/ myotube hypertrophy. 15,17,18,32 TE671/RAGE cells show increased extents of phosphorylation (activation) of the promyogenic p38 MAPK and Akt, and HMGB1 further increases them. Thus, a relationship exists in TE671/ RAGE cells among RAGE expression, p38 MAPK and Akt activation, up-regulation of myogenin and MHC expression, induction of MCK, and cell hypertrophy.…”

“…5,15,17,18 Transfection of TE671/RAGE cells with MKK6AA, a functionally inactive mutant of MKK6, resulted in a reduced MCK induction irrespective of the absence or presence of added HMGB1 ( Figure 3A), suggesting that the MKK6/p38 MAPK pathway was involved in the myogenic program activated by HMGB1/RAGE. Switching TE671/RAGE cells from growth medium (GM, 5% FBS) to DM consistently caused a sustained activation of p38 MAPK ( Figure 3B), and administration of HMGB1 caused a further increase in p38 MAPK activation at an early time point ( Figure 3C).…”

Highly efficient derivation of ventricular cardiomyocytes from induced pluripotent stem cells with a distinct epigenetic signature

“…This hypothesis is consistent with mechanism of action of the DNA demethylating agent, 5-azacytidine, which has been used to induce cardiomyogenic gene expression in Sca-1 + cardiovascular progenitors [32] and human ESCs [26]. Moreover, DNA demethylation has been implicated in the epigenetic regulation of skeletal muscle specification [33,34]. While a number of significant challenges remain, the findings here suggest that the reprogramming of human VMs to human ViPSCs may be a tractable strategy of deriving large numbers of VMs for cardiac regenerative medicine.…”

Differential expression of the HMGN family of chromatin proteins during ocular development

“…In recent years, it has been demonstrated that precise control of the chromatin structure of specific genes is crucial for the maintenance of the pluripotency of the inner cell mass (Boyer et al, 2006), while remodeling of chromatin is crucial for the commitment of these cells to specific lineages during development (Kondo, 2006), and their final terminal differentiation (Ehrlich, 2003;Hsieh and Gage, 2004;Palacios and Puri, 2006;Wilson et al, 2005;Zhou et al, 2005). The molecular mechanisms controlling the chromatin structure of genes has been under intense investigation and has been found to result from numerous epigenetic modifications including the differential regulation of histone acetylation, methylation and phosphorylation, DNA methylation and the use of histone variants in the nucleosomal structure (Wegel and Shaw, 2005).…”