Jarid2 (Jumonji, AT Rich Interactive Domain 2) Regulates NOTCH1 Expression via Histone Modification in the Developing Heart

Mysliwiec, Matthew R.; Carlson, Clayton D.; Tietjen, Josh; Hung, Holly A.; Ansari, Aseem Z.; Lee, Youngsook

doi:10.1074/jbc.m111.315945

Cited by 61 publications

(66 citation statements)

References 30 publications

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“…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.…”

Section: Discussionsupporting

confidence: 82%

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

et al. 2013

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SUMMARYTrabeculation and compaction of the embryonic myocardium are morphogenetic events crucial for the formation and function of the ventricular walls. Fkbp1a (FKBP12) is a ubiquitously expressed cis-trans peptidyl-prolyl isomerase. Fkbp1a-deficient mice develop ventricular hypertrabeculation and noncompaction. To determine the physiological function of Fkbp1a in regulating the intercellular and intracellular signaling pathways involved in ventricular trabeculation and compaction, we generated a series of Fkbp1a conditional knockouts. Surprisingly, cardiomyocyte-restricted ablation of Fkbp1a did not give rise to the ventricular developmental defect, whereas endothelial cell-restricted ablation of Fkbp1a recapitulated the ventricular hypertrabeculation and noncompaction observed in Fkbp1a systemically deficient mice, suggesting an important contribution of Fkbp1a within the developing endocardia in regulating the morphogenesis of ventricular trabeculation and compaction. Further analysis demonstrated that Fkbp1a is a novel negative modulator of activated Notch1. Activated Notch1 (N1ICD) was significantly upregulated in Fkbp1a-ablated endothelial cells in vivo and in vitro. Overexpression of Fkbp1a significantly reduced the stability of N1ICD and direct inhibition of Notch signaling significantly reduced hypertrabeculation in Fkbp1a-deficient mice. Our findings suggest that Fkbp1a-mediated regulation of Notch1 plays an important role in intercellular communication between endocardium and myocardium, which is crucial in controlling the formation of the ventricular walls.KEY WORDS: FK506 binding protein 12, Ventricular hypertrabeculation/noncompaction, Notch1, Endocardial-myocardial signaling, Mouse

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Section: Discussionsupporting

confidence: 82%

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

et al. 2013

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“…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.…”

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confidence: 99%

Epigenetic Regulation of Angiogenesis by JARID1B-Induced Repression of HOXA5

Fork

Hitzel

et al. 2015

ATVB

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Objective-Altering endothelial biology through epigenetic modifiers is an attractive novel concept, which is, however, just in its beginnings. We therefore set out to identify chromatin modifiers important for endothelial gene expression and contributing to angiogenesis. Approach and Results-To identify chromatin modifying enzymes in endothelial cells, histone demethylases were screened by microarray and polymerase chain reaction. The histone 3 lysine 4 demethylase JARID1B was identified as a highly expressed enzyme at the mRNA and protein levels. Knockdown of JARID1B by shRNA in human umbilical vein endothelial cells attenuated cell migration, angiogenic sprouting, and tube formation. Similarly, pharmacological inhibition and overexpression of a catalytic inactive JARID1B mutant reduced the angiogenic capacity of human umbilical vein endothelial cells. To identify the in vivo relevance of JARID1B in the vascular system, Jarid1b knockout mice were studied. As global knockout results in increased mortality and developmental defects, tamoxifen-inducible and endothelial-specific knockout mice were generated. Acute knockout of Jarid1b attenuated retinal angiogenesis and endothelial sprout outgrowth from aortic segments. To identify the underlying mechanism, a microarray experiment was performed, which led to the identification of the antiangiogenic transcription factor HOXA5 to be suppressed by JARID1B. Importantly, downregulation or inhibition of JARID1B, but not of JARID1A and JARID1C, induced HOXA5 expression in human umbilical vein endothelial cells. Consistently, chromatin immunoprecipitation revealed that JARID1B occupies and reduces the histone 3 lysine 4 methylation levels at the HOXA5 promoter, demonstrating a direct function of JARID1B in endothelial HOXA5 gene regulation. Conclusions-JARID1B, by suppressing HOXA5, maintains the endothelial angiogenic capacity in a demethylasedependent manner.

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“…This view is also supported by the finding that JARID2 regulates Notch1 expression in the developing heart, probably by interacting with the methyltransferase SETDB1, which methylates H3K9. 17 Furthermore, JARID2 inhibits cardiomyocyte proliferation, 18 which raises the question of whether lack of EZH2 increases the levels of "free" JARID2, which, together with the increased concentration of Ink4a/b that was observed by He et al 6 …”

Section: Further Chromatin Immunoprecipitation Experiments In Ezh2mentioning

confidence: 99%

When Silence is Broken

Dobreva

Braun

2012

Circulation Research

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Jarid2 (Jumonji, AT Rich Interactive Domain 2) Regulates NOTCH1 Expression via Histone Modification in the Developing Heart

Cited by 61 publications

References 30 publications

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

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

Epigenetic Regulation of Angiogenesis by JARID1B-Induced Repression of HOXA5

When Silence is Broken

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