Abstract 3812: The Role of the E2F6 Transcription Repressor in Dilated Cardiomyopathy
The E2F family of transcription factors plays a key role in important biological processes including cell differentiation, growth, and death. We evaluated the importance of the E2F6 repressor, which is known to repress E2F responsive genes, in the mammalian heart using a transgenic (Tg) mouse model with altered levels of E2F6. We hypothesize that a proper balance of E2F mediated activation of genes tempered by E2F6 mediated repression is necessary for proper heart development and function. Mice which over express the E2F6 protein develop dilated cardiomyopathy (DCM) characterized by a significantly reduced ejection fraction (<40%) as well as significant end systolic and diastolic dilation. Furthermore, these mice begin to die at a young adult age (<3months). Microarray analysis of these mice led to the identification of 110 genes which were significantly deregulated in Tg mice. Quantitative real-time PCR confirmed a number of these genes including cardiac troponin (Tnnt2) and the potassium rectifying channel (Kcne1), which are down regulated ~2.8 (+/−0.08) and ~2.7(+/−0.1) fold respectively. The transcription factor Max gene associated (Mga), which interacts with E2F6 in a repression complex, is up-regulated ~2.5 (+/−0.7) fold (n=3–5). PANTHER functional analysis of the identified genes revealed a significant enrichment of down-regulated genes involved in developmental processes and cell communication (16 and 12 genes respectively), which are of critical importance for proper heart development and response to the environment. In addition, four genes involved in muscle contraction are also significantly down-regulated. Moreover, protein levels of the cardiac calcium pump (SERCA2), cardiac troponin (TnI), and ventricular gap junction protein (Cx43) are markedly decreased, providing a potential mechanism for the observed decrease in contractile force, which could progressively lead to the development of DCM. In contrast, genes and proteins involved in cell structure and motility such as vinculin (Vcl) and actin are up-regulated in Tg mice. Thus, our data suggests that the E2F6 repressor may be important for modulating the E2F pathway and regulating levels of gene expression required for normal cardiac development and function.
(Funded by CIHR.)