Abstract 21584: Jarid2/Jumonji Dependent Epigenetic Control of Notch1 Expression is Required for Normal Cardiac Development
Jarid2/Jumonji critically regulates developmental processes including cardiovascular development. Jarid2 knockout mice exhibit cardiac defects including hyper-trabeculae with noncompaction of the ventricular wall. Jarid2 is the founding member of the Jmj factor family containing a JmjC domain that has been recently shown to function as histone demethylases, indicating epigenetic regulation by Jmj proteins. However, molecular mechanisms underlying Jarid2-mediated cardiac development remain unknown. To determine the lineage-specific roles of Jarid2, we generated myocardial, epicardial, cardiac neural crest, or endocardial conditional Jarid2 knockout mice using Cre-loxP technology. Only mice with an endothelial deletion of Jarid2 recapitulate phenotypic defects observed in whole body mutants including hyper-trabeculation and noncompaction of the ventricle. Whole body or endocardial deletion of Jarid2 leads to increased endocardial Notch1 expression in the developing ventricle, which results in increased Notch1-dependent signaling to the adjacent myocardium. Using quantitative chromatin immunoprecipitation analysis on hearts, Jarid2 was found to occupy a previously unidentified region on the endogenous Notch1 locus. Whole body or endocardial deletion of Jarid2 resulted in reduced methylation of lysine 9 on histone H3 at the site of Jarid2 occupancy in the developing heart. Further, we show that Jarid2 directly interacts with the histone methylase Setdb1 and is required for recruitment of Setdb1 to the endogenous Notch1 locus. We propose that failure to properly regulate Notch signaling in Jarid2 mutants leads to the defects in the developing ventricular chamber. Thus, Jarid2 functions as a transcriptional repressor through epigenetic modification of target genes via recruitment of histone modifying partners. The identification of Jarid2 as a direct regulator of Notch1 signaling has broad implications for many cellular processes including development, stem cell maintenance, and tumor formation.
- © 2010 by American Heart Association, Inc.