Abstract 118: Role Of Histone Trimethyl Demethylase Jmjd2A In Cardiac Hypertrophy And Heart Development

Abstract

Epigentic regulation via histone memethylation has been shown to play important role in embryonic development and pathogenesis of adult diseases. Methylation of histone H3 lysine 9 (H3K9) mediates heterochromatin formation and also 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. Histone demethylases for methylated H3K9 have been shown to play important role in tumorigenesis. However, their roles in 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 and the demethylase activity of Jmjd2A is required for its transcriptional activity. Jmjd2A also plays an important role during embryonic development. Mice with homozygous deletion of Jmjd2A exhibit partial embryonic lethality depending on the genetic background. In C57Bl6 (N>5) mouse strain, some of the Jmjd2A-null embryos die between embryonic day E10-E12 with heart failure phenotype. Deletion of Jmjd2A appears to have no effect on formation of linear heart tube and subsequent looping at E9.5. However, while WT or Jmjd2A het 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. These failing hearts show reduced cardiomyocyte proliferation. Gene expression profiling suggests potential downstream effectors of Jmjd2A including cell cycle and “immediate early” genes. 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.