| ERG belongs to the ETS family of transcription factors, which bind specific DNA sequences to control gene expression during development and cell growth. It has a key ETS DNA-binding domain at the C-terminus and an N-terminal region that activates transcription through interactions with other proteins. ERG drives gene programs by binding ETS motifs in promoters and enhancers, often partnering with RUNX1 to co-occupy chromatin and activate endothelial genes such as VEGFR2 and Tie2, while repressing others through epigenetic silencing via histone deacetylases. ERG integrates signals from VEGF/PI3K pathways to maintain vascular integrity, promoting junctional remodeling via VE-cadherin regulation and shear-stress responses that fine-tune arterial-venous specification in endothelial cells. During hematopoiesis, ERG sustains stem cell pluripotency by counteracting differentiation cues from GATA2 and FLI1, ensuring balanced output of erythroid, myeloid, and megakaryocytic lineages. This dual role in vascular and blood development makes ERG essential for studying tissue specification where lineage fidelity meets environmental cues. Chromosomal fusions like EWSR1-ERG in Ewing sarcoma hijack ERG's pointed domain for aberrant super-enhancer formation, driving IGF1R/GLI1 expression and sarcomagenesis, while TMPRSS2-ERG fusions in prostate cancer amplify androgen-driven proliferation through MYC/AR pathway hijacking and PTEN loss synergy. Normal ERG expression persists in adult endothelial beds, with post-translational control via MAPK phosphorylation modulating its activity in angiogenesis and inflammation. |
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