Mechanism of Egr-1 control of cardiac calcium homeostasis

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Egr-1 overexpressing cardiac cells have repressed calcium dynamics linked to reduced calsequestrin 2 (CSQ2) expression (Kasneci et al App 1). We found Egr-1 to repress CSQ2 expression by a novel mechanism. Egr-1 binds rat and mouse CSQ2 promoter DNA at a 165 bp region that is >75% homologous between the 2 species and contains Egr-1 and SP1 consensus sites overlapping a CpG island. Egr-1 is known to bind to SP1, p300/CBP and casein kinase II, is phosphorylated by PKA, PKC and CKII and acetylated by p300/CBP. Whether these modifications or interactions promote activation or repression depends upon the promoter analyzed and tissue/cell type used. We hypothesize that Egr-1 displaces activating SP1 to repress CSQ2. Because Egr-1's action is context dependent we hypothesize that the Egr-1 modifications and the Egr-1 complexes formed with existing protein:DNA complexes and/or DNA/chromatin modifiers at the repressed CSQ2 promoter are particular to cardiac cells.