Abstract 11367: Role of Histone Trimethyl Demethylase JMJD2A in Cardiac Hypertrophy and Heart Development
Epigentic regulation via histone methylation has been shown to play important role in embryonic development and pathogenesis of adult diseases. Methylation of histone H3 lysine 9 (H3K9) participates in inhibition of gene transcription at euchromatic sites. Methylation of H3K9 is required for proper embryonic development as shown by various genetic studies of H3K9 methyltransferases in mice. However, the roles of histone demethylases in cardiovascular development and in adult cardiovascular diseases remain elusive. JMJD2A is H3K9me3 specific demethylase. To study its biological functions, we generated mouse with conditional alleles of JMJD2A. Our studies with post-natal heart specific JMJD2A deletion and overexpression mouse lines indicated that JMJD2A is required for pathological cardiac hypertrophy induced by thoracic aortic constriction. JMJD2A also plays an important role during embryonic development. Mice with general homozygous deletion of JMJD2A exhibit partial embryonic lethality depending on the genetic background. In C57/BL6 (N>5) mouse strain, some of JMJD2A-null embryos die between embryonic day E10-E12 with a spectrum of heart developmental defect and heart failure phenotypes. Deletion of JMJD2A appears to have no effect on formation of linear heart tube and subsequent looping (E9.5). However, while WT or JMJD2A heterogeneous hearts continue to grow with appearance of ventricular and atrial septum and formation of trabeculae, JMJD2A-null embryonic hearts have pericardial effusion, thin myocardium, lack of atrial and ventricular septation, and under-developed trabaculae. The failing hearts show reduced cardiomyocyte proliferation. Gene expression profiling suggests potential downstream effectors of JMJD2A including cell cycle and proliferation related genes. Of significance, Wnt5a gene, which regulates secondary heart field progenitor cell differentiation, is down regulated in knockout heart as confirmed by real-time PCR and in situ hybridization. Our data demonstrate that JMJD2A plays important roles during heart development and functions as a hypertrophic determinant in response to pathological stimuli in adult hearts.
- © 2013 by American Heart Association, Inc.