Abstract 118: Epigenetic Regulation of Ventricular Development

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Perturbations of the epigenetic machinery can lead to the deregulation of cardiac gene expression, resulting in defective cardiac development and cardiac hypertrophy. Due to a groundbreaking discovery of histone demethylases such as Jumonji (Jmj) family factors, histone methylation is now considered as a reversible epigenetic mark. Jarid2/Jumonji is the founding member of the JMJ family. Jarid2 is enzymatically inactive, but functions as a transcriptional regulator. Jarid2 critically regulates cardiovascular development as well as ES cell differentiation and generation of iPS cells. Jarid2 knockout (KO) mice exhibit cardiac defects including hyper-trabeculation with noncompaction of the ventricular wall. Although Jarid2 interacts with Polycomb Repressor Complex in ES cells, the precise function of Jarid2 in cardiac development remains to be determined. Therefore, we set out to determine molecular mechanisms of Jarid2 critical for cardiac development. To identify cardiac-specific roles of Jarid2, we generated deletion of Jarid2 in early cardiac progenitors using Nkx2.5-Cre Knock-in mice (Jarid2Nkx-KI). Jarid2Nkx-KI mice recapitulate partial phenotypic defects observed in Jarid2 KO including hyper-trabeculation, thin myocardium and ventricular septal defects. By overlapping ChIP-chip and microarray analyses, we have identified potential transcriptional targets of Jarid2, which are occupied by Jarid2, SETDB1, H3K9me3 or H3K27me3, and upregulated in Jarid2 mutant hearts. 174 genes including Isl1 were identified as dysregulated genes that showed accumulation of Jarid2 and H3K27me3. 172 genes including Bmp10 were identified as dysregulated genes and were occupied by Jarid2, SETDB1 and H3K9me3. Isl1, Bmp10/p-Smad1/5/8, and Ifgbp2 were upregulated in Jarid2Nkx-KI hearts by qRT-PCR and Western blotting. Islet1 plays crucial roles in early cardiac development and a marker for cardiac progenitors. Jarid2 occupancy was observed at the Isl1 promoter region by ChIP assays in WT hearts, which was reduced in Jarid2Nkx-KI. All together, our data indicate that Jarid2 regulates target gene expression by interacting with different histone modifiers depending on the cell/promoter context, which is critical for ventricular wall maturation.

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