Abstract
Initiation of and progression through chondrogenesis is driven by changes in the cellular microenvironment. At the onset of chondrogenesis, resting mesenchymal stem cells are mobilized in vivo and a complex, step-wise chondrogenic differentiation program is initiated. Differentiation requires coordinated transcriptomic reprogramming and increased progenitor proliferation; both processes require chromatin remodeling. The nature of early molecular responses that relay differentiation signals to chromatin is poorly understood. We here show that immediate early genes are rapidly and transiently induced in response to differentiation stimuli in vitro. Functional ablation of the immediate early factor EGR1 severely deregulates expression of key chondrogenic control genes at the onset of differentiation. In addition, differentiating cells accumulate DNA damage, activate a DNA damage response and undergo a cell cycle arrest and prevent differentiation associated hyper-proliferation. Failed differentiation in the absence of EGR1 affects global acetylation and terminates in overall histone hypermethylation. We report novel molecular connections between EGR1 and Polycomb Group function: Polycomb associated histone H3 lysine27 trimethylation (H3K27me3) blocks chromatin access of EGR1. In addition, EGR1 ablation results in abnormal Ezh2 and Bmi1 expression. Consistent with this functional interaction, we identify a number of co-regulated targets genes in a chondrogenic gene network. We here describe an important role for EGR1 in early chondrogenic epigenetic programming to accommodate early gene-environment interactions in chondrogenesis.
Highlights
Differentiation requires orchestration of numerous parallel cellular responses and altered physiological states associated with the novel cell fate
Egr1 is rapidly induced in chondrogenesis To identify immediate early growth response gene (IEG)
Expression array analysis revealed rapid upregulation of a number of immediate early genes (IEG): expression of genes belonging to the Fos, Jun and Egr subfamilies (Egr1, Egr2, Egr3, FosB, Fosl1, cFos, cJun, JunB, JunD) was significantly enhanced within 2 hours post-induction of differentiation (Figure 1A)
Summary
Differentiation requires orchestration of numerous parallel cellular responses and altered physiological states associated with the novel cell fate Such changes are often induced by environmental cues (i.a. soluble factors, cell-cell contacts), that are transduced to the nucleus and translated into spatio-temporal reprofiling of gene expression. On their way to becoming terminally differentiated chondrocytes, chondrogenic progenitor cells undergo a well-described sequential series of events at the cell biology level: initially resting growth plate stem cells undergo a transient replicative burst. Pathways and mechanisms involved in chondrogenesis are continuously being defined, important issues surrounding the most primary steps in chondrogenic commitment and differentiation remain to be elucidated This includes what connects environmental cues to chromatin and which signaling factors are involved in early epigenomic remodeling and, in differentiation
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