Endothelial Jarid2/Jumonji Is Required for Normal Cardiac Development and Proper Notch1 Expression

Abstract

Jarid2/Jumonji critically regulates developmental processes including cardiovascular development. Jarid2 knock-out mice exhibit cardiac defects including hypertrabeculation with noncompaction of the ventricular wall. However, molecular mechanisms underlying Jarid2-mediated cardiac development remain unknown. To determine the cardiac lineagespecific roles of Jarid2, we generated myocardial, epicardial, cardiac neural crest, or endothelial 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 hypertrabeculation and noncompaction of the ventricle. To identify potential targets of Jarid2, combinatorial approaches using microarray and candidate gene analyses were employed on Jarid2 knock-out embryonic hearts. Whole body or endothelial deletion of Jarid2 leads to increased endocardial Notch1 expression in the developing ventricle, resulting in increased Notch1-dependent signaling to the adjacent myocardium. Using quantitative chromatin immunoprecipitation analysis, Jarid2 was found to occupy a specific region on the endogenous Notch1 locus. We propose that failure to properly regulate Notch signaling in Jarid2 mutants likely leads to the defects in the developing ventricular chamber. The identification of Jarid2 as a potential regulator of Notch1 signaling has broad implications for many cellular processes including development, stem cell maintenance, and tumor formation.The heart is the first organ to form and function during embryogenesis. Improper formation of the heart leads to congenital heart defects, which are the most common form of human birth defects (1, 2). The formation of the heart is a complex process that requires delicate spatial and biochemical interactions among various cell types. Despite extensive studies to determine the transcriptional regulation of cardiac development, the precise mechanisms of ventricular chamber development remain largely unknown. Mice with a homozygous Jarid2 deletion (Jarid2 KO) exhibit cardiac defects mimicking human congenital cardiac defects including ventricular septal defects (VSD), 2 double outlet right ventricle (DORV), and hypertrabeculation associated with noncompaction of the ventricular wall resulting in a thin compact layer (3, 4). These mutant mice survive until birth and offer the unique opportunity to further explore the molecular mechanisms of development and late stage maturation of the ventricular chamber.Jarid2 is the founding member of the Jumonji family of proteins, all of which contain the JmjC domain that was first defined based on amino acid similarities between Jarid2, Jarid1C (Smcx), and Jarid1A (RBP2) (5-7). Proteins containing the JmjC domain generally function as histone demethylases (8). Intriguingly, Jarid2 contains mutations at key amino acids necessary for enzymatic function and is highly likely enzymatically inactive (9 -11). Recent evidence suggests that Jarid2 plays critical roles in the regulation of gene express...

Fkbp1a controls ventricular myocardium trabeculation and compaction by regulating endocardial Notch1 activity

“…Our findings suggest that Fkbp1a has a role in regulating endocardial Notch1 activity, which is crucial to ventricular wall formation. Our findings are entirely consistent with recent reports by Mysliwiec and colleagues that upregulation of Notch1 in endocardial cells leads to ventricular hypertrabeculation and noncompaction (Mysliwiec et al, 2011;Mysliwiec et al, 2012). Most recently, Yang and colleagues demonstrated that upregulated Notch2 activity in Numb/Numb-like compound deficient mutants contributes to Bmp10 upregulation and ventricular hypertrabeculation and noncompaction phenotypes (Yang et al, 2012), further validating our conclusion.…”

Epigenetic Modification at Notch Responsive Promoters Blunts Efficacy of Inducing Notch Pathway Reactivation After Myocardial Infarction

“…46 Also in the developing myocardium, endothelial deletion of Jarid2, a member of the Jumonji family of proteins that is not active as a demethylase but associates with the PcG complex to modulate its function, 47,48 derepresses endocardial Notch1 expression. 49 In addition, deletion of Ezh2 in cardiac progenitors is known to cause postnatal myocardial pathology. 50 In neonatal cardiomyocytes, chromatin-mediated suppression of the Notch target genes was effectively counteracted by the forced activation of the Notch pathway on AAV-mediated gene transfer.…”

Epigenetic Regulation of Angiogenesis by JARID1B-Induced Repression of HOXA5

“…8 For JARID2, an important role of endocardial-driven cardiac development has been reported. 9,10 The function of the other JARID enzymes in the cardiovascular system has not been studied. In this study, we found the enzyme JARID1B, which has been implicated in cell fate decision, cancer progression, and stem cell self-renewal, 5,[11][12][13] to be highly expressed in ECs.…”