jumonji Downregulates Cardiac Cell Proliferation by Repressing cyclin D1 Expression

Abstract

Spatiotemporal regulation of cell proliferation is necessary for normal tissue development. The molecular mechanisms, especially the signaling pathways controlling the cell cycle machinery, remain largely unknown. Here, we demonstrate a negative relationship between the spatiotemporal patterns of jumonji (jmj) expression and cardiac myocyte proliferation. cyclin D1 expression and cell proliferation are enhanced in the cardiac myocytes of jmj-deficient mutant embryos. In contrast, jmj overexpression represses cyclin D1 expression in cardiac cells, and Jmj protein binds to cyclin D1 promoter in vivo and represses its transcriptional activity. cyclin D1 overexpression causes hyperproliferation in the cardiac myocytes, but the absence of cyclin D1 in jmj mutant embryos rescues the hyperproliferation. Therefore, Jmj might control cardiac myocyte proliferation and consequently cardiac morphogenesis by repressing cyclin D1 expression.

Roles of jumonji and jumonji family genes in chromatin regulation and development

“…Cardiac myocytes in trabecular layer showed hyperproliferation in our jmj mutant mice Toyoda et al, 2003). From analysis of the hyperproliferation, we found that jmj expression starts at the stages when cell proliferation of cardiac myocytes starts to decrease in normal embryos and that cell proliferation and expression of cyclin D1, the gene that encodes one of the G1 cyclins, are not repressed in jmj embryos (Toyoda et al, 2003). jmj overexpression by transgenesis represses cyclin D1 expression in the heart.…”

“…For example, strong expression can be detected in many neurons after final mitosis in the cerebrum and cerebellum (Takeuchi et al, 1995;Takeuchi, 1997). jmj expression starts when the levels of cell proliferation start to decrease in cardiac myocytes in the ventricles (Toyoda et al, 2003). A more typical expression pattern can be seen in the lens (Fig.…”

“…Hairless functions as a nuclear receptor corepressor (Potter et al, 2001). In addition, mouse Jmj protein was shown to be a transcriptional repressor that directly represses cyclin D1 expression (Toyoda et al, 2003). Lee's group also reported that Jmj is a transcriptional repressor that can repress the promoter activities of atrial natriuretic factor and alpha-cardiac myosin heavy chain genes (Kim et al, 2003(Kim et al, , 2004.…”

“…Lee's group also reported that Jmj is a transcriptional repressor that can repress the promoter activities of atrial natriuretic factor and alpha-cardiac myosin heavy chain genes (Kim et al, 2003(Kim et al, , 2004. The region that is necessary for the repression is located in the N-terminal of Jmj (Kim et al, 2003;Toyoda et al, 2003). Further roles of the region are unknown; however, it is possible that the region binds to cofactors involved in repression, such as histone modification.…”

“…We have demonstrated previously that Jmj is a transcriptional repressor and represses cyclin D1 transcription in the embryonic heart and that this repression is required for normal cardiogenesis (Toyoda et al, 2003). Several reports also suggested that jumonji family members are involved in transcriptional or chromatin regula-tion.…”