Myc regulates keratinocyte adhesion and differentiation via complex formation with Miz1

Myc plays a key role in homeostasis of the skin. We show that Miz1, which mediates Myc repression of gene expression, is expressed in the epidermal basal layer. A large percentage of genes regulated by the Myc-Miz1 complex in keratinocytes encode proteins involved in cell adhesion, and some, including the alpha6 and beta1 integrins, are directly bound by Myc and Miz1 in vivo. Using a Myc mutant deficient in Miz1 binding (MycV394D), we show that Miz1 is required for the effects of Myc on keratinocyte responsiveness to TGF-beta. Myc, but not MycV394D, decreases keratinocyte adhesion and spreading. In reconstituted epidermis, Myc induces differentiation and loss of cell polarization in a Miz1-dependent manner. In vivo, overexpression of beta1 integrins restores basal layer polarity and prevents Myc-induced premature differentiation. Our data show that regulation of cell adhesion is a major function of the Myc-Miz1 complex and suggest that it may contribute to Myc-induced exit from the epidermal stem cell compartment.     

Inhibition of the terminal stages of adipocyte differentiation by cMyc

The nuclear oncoprotein Myc is a pivotal regulator of several important biological processes, including cellular proliferation, differentiation, and apoptosis. Deregulated Myc expression is incompatible with terminal differentiation in a variety of cell types, including adipocytes. To understand how Myc inhibits adipogenesis, we analyzed the effect of Myc on the expression of genes characteristic of distinct phases of the hormonally induced adipogenic differentiation program in 3T3-L1 preadipocytes. We show that the early regulators, C/EBPbeta and C/EBPdelta, are induced normally in response to hormone in 3T3-L1 preadipocytes constitutively expressing Myc, but that expression of the downstream regulators, C/EBPalpha and PPARgamma2, and later markers of differentiation is suppressed. These data demonstrate that Myc specifically inhibits the terminal stages of the adipogenic program and suggest that Myc may act by blocking C/EBPbeta- and C/EBPdelta-directed activation of C/EBPalpha and PPARgamma2 expression, although the precise molecular mechanism is not understood. Surprisingly, a serum component(s) could override the Myc-induced differentiation block, suggesting that the ability of a cell to undergo terminal differentiation is governed by the action of both positive and negative factors. Since differentiation and proliferation are mutually exclusive events, this has important implications since it may be possible to force malignant cells along a differentiation pathway, thereby curbing their proliferative potential.     

Long noncoding RNA lncMREF promotes myogenic differentiation and muscle regeneration by interacting with the Smarca5/p300 complex

Long noncoding RNAs (lncRNAs) play important roles in the spatial and temporal regulation of muscle development and regeneration. Nevertheless, the determination of their biological functions and mechanisms underlying muscle regeneration remains challenging. Here, we identified a lncRNA named lncMREF (lncRNA muscle regeneration enhancement factor) as a conserved positive regulator of muscle regeneration among mice, pigs and humans. Functional studies demonstrated that lncMREF, which is mainly expressed in differentiated muscle satellite cells, promotes myogenic differentiation and muscle regeneration. Mechanistically, lncMREF interacts with Smarca5 to promote chromatin accessibility when muscle satellite cells are activated and start to differentiate, thereby facilitating genomic binding of p300/CBP/H3K27ac to upregulate the expression of myogenic regulators, such as MyoD and cell differentiation. Our results unravel a novel temporal-specific epigenetic regulation during muscle regeneration and reveal that lncMREF/Smarca5-mediated epigenetic programming is responsible for muscle cell differentiation, which provides new insights into the regulatory mechanism of muscle regeneration.