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Embryonic VHL-HIF signaling defines dynamic heart metabolic compartments essential for cardiac maturation

ABSTRACT: While gene regulatory networks involved in cardiogenesis have been characterized, the role of bioenergetics remains less studied. Here we show that until midgestation, myocardial metabolism is compartmentalized, with a glycolytic signature restricted to compact myocardium contrasting with increased mitochondrial oxidative activity in the trabeculae. HIF1a regulation mirrors this pattern, with expression predominating in compact myocardium and scarce in trabeculae. By midgestation, the compact myocardium downregulates HIF1a and switches toward oxidative metabolism. Deletion of the E3 ubiquitin ligase Vhl results in HIF1a hyperactivation, disrupting metabolic compartmentalization and blocking the midgestational shift toward oxidative phosphorylation. Moreover, the altered glycolytic signature induced by HIF1 trabecular activation precludes regulation of genes essential for cardiac conduction system establishment. Our findings reveal VHL-HIF-mediated metabolic compartmentalization in the developing heart and the connection between metabolism and myocardial differentiation. These results highlight the importance of bioenergetics in ventricular myocardium specialization and its potential relevance to congenital heart disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE89733 | GEO | 2016/12/19

SECONDARY ACCESSION(S): PRJNA353028

REPOSITORIES: GEO

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Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy

Project description:Left ventricular noncompaction (LVNC) Causes prominent ventricular trabeculations and reduces cardiac systolic function. The clinical presentation of LVNC ranges from asymptomatic to heart failure. We show that germline mutations in human MIB1 (mindbomb homolog 1), which encodes an E3 ubiquitin ligase that promotes endocytosis of the NOTCH ligands DELTA and JAGGED, cause LVNC in autosomal-dominant pedigrees, with affected individuals showing reduced NOTCH1 activity and reduced expression of target genes. Functional studies in cells and zebrafish embryos and in silico modeling indicate that MIB1 functions as a dimer, which is disrupted by the human mutations. Targeted inactivation of Mib1 in mouse myocardium causes LVNC, a phenotype mimicked by inactivation of myocardial Jagged1 or endocardial Notch1. Myocardial Mib1 mutants show reduced ventricular Notch1 activity, expansion of compact myocardium to proliferative, immature trabeculae and abnormal expression of cardiac development and disease genes. These results implicate NOTCH signaling in LVNC and indicate that MIB1 mutations arrest chamber myocardium development, preventing trabecular maturation and compaction. RNA was isolated from the ventricles of 16 WT and 16 Mib1flox; CTnT-cre hearts at E14.5 and then pooled into four replicates.

2015-08-10 | E-GEOD-71912 | biostudies-arrayexpress

Mus musculus

Project description:Microarray characterization of Vhl; Vhl, Hif1a; Vhl, Hif2a and Vhl, Hif1a, Hif2a deficient primary kidney cells

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Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy

2015-08-10 | GSE71912 | GEO

HIF1a-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells

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2011-06-07 | E-GEOD-29765 | biostudies-arrayexpress

SIRT3 opposes metabolic reprogramming of cancer cells through HIF1a destabilization

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2011-03-15 | E-GEOD-27309 | biostudies-arrayexpress

RNA seq of vhlfl/fl cd4 cre, hif1afl/fl vhlfl/fl cd4 cre and WT CD4 T cells before and after anti-CD3/CD28 stimulation

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Project description:Hypermethylation of tumor suppressors and other aberrations of DNA methylation in tumors play a significant role in cancer progression. DNA methylation can be affected by various environmental conditions including hypoxia. The response to hypoxia is mainly achieved through activation of the transcription program associated with HIF1a transcription factor. VHL inactivation by genetic or epigenetic events, which also induces aberrant activation of HIF1a, is the most common driver event for renal cancer. With whole-genome bisulfite sequencing and LC-MS, we demonstrated that VHL inactivation induced global genome hypermethylation in human kidney cancer cells under normoxic conditions. This effect was reverted by exogenous expression of wild-type VHL. We show that global genome hypermethylation in VHL mutants can be explained by the accumulation of 2-hydroxyglutarate -- a metabolite that inhibits DNA demethylation by Tet enzymes.

2021-06-01 | GSE151787 | GEO

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Project description:IMV induces transcription of key glycolytic enzymes in alveolar epithelial type II mice IMV induced transcription of key glycolytic enzymes is HIF1A dependent

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