Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of mouse fetal heart from wild type and Estrogen-related Receptor gamma (ERRg) knockout strains

ABSTRACT: 3 ventricles from E18.5 male mice were pooled for each array. Three arrays per genotype. Title: ERRÎ³ Directs and Maintains the Transition to Oxidative Metabolism in the Post-Natal Heart; Abstract: At birth the heart undergoes a critical metabolic switch to transition from a predominant dependence on carbohydrates during fetal life to a greater dependence on postnatal oxidative metabolism. This remains the principle metabolic state throughout life; although pathologic conditions such as heart failure and cardiac hypertrophy reactivate components of the fetal genetic program to increase carbohydrate utilization. Disruption of the ERRÎ³ gene, which is expressed at high levels in the fetal and postnatal mouse heart, blocks this switch resulting in lactatemia, electrocardiographic (ECG) abnormalities and death during the first week of life. Genomic ChIP-on-chip and expression analysis at E18.5 clearly identifies ERRÎ³ as both a direct and indirect regulator of a nuclear-encoded mitochondrial genetic network that coordinates the postnatal metabolic transition. These findings reveal an unexpected and essential molecular genetic component of the oxidative metabolic gene program in the heart and highlight ERRÎ³ in the study of cardiac hypertrophy and failure. Experiment Overall Design: Fetal mice were collected by caesarean secation. Hearts were stored in RNALater (Qiagen)

ORGANISM(S): Mus musculus

SUBMITTER: Ronald Evans

PROVIDER: E-GEOD-8199 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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ERRgamma directs and maintains the transition to oxidative metabolism in the postnatal heart.

Alaynick William A WA Kondo Richard P RP Xie Wen W He Weimin W Dufour Catherine R CR Downes Michael M Jonker Johan W JW Giles Wayne W Naviaux Robert K RK Giguère Vincent V Evans Ronald M RM

Cell metabolism 20070701 1

At birth, the heart undergoes a critical metabolic switch from a predominant dependence on carbohydrates during fetal life to a greater dependence on postnatal oxidative metabolism. This remains the principle metabolic state throughout life, although pathologic conditions such as heart failure and cardiac hypertrophy reactivate components of the fetal genetic program to increase carbohydrate utilization. Disruption of the ERRgamma gene (Esrrg), which is expressed at high levels in the fetal and ...[more]

PMID: 17618853

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Project description:The heart undergoes significant structural, metabolic, gene expression and functional alterations during the perinatal to postnatal transition. While recent studies have identified multiple epigenetic and transcriptional regulators of cardiac maturation, post-transcriptional mechanisms regulating this process remain poorly understood. Neddylation is a post-translational modification that conjugates a small ubiquitin-like protein, NEDD8, to protein substrates via an E1-E2-E3 enzymatic cascade. The goal of this study was to define the role of neddylation in perinatal cardiac development and cardiac maturation. Neddylation was inhibited in adult mouse hearts by cardiac-specific deletion of NAE1 gene, a regulatory subunit of NEDD8 E1 enzyme, or in neonatal cardiomyocytes (CMs) with a pharmacological neddylation inhibitor, MLN4924. The impact on cardiac transcriptome, metabolism, maturation and function was assessed. Mosaic deletion of NAE1 in ~40% neonatal CMs disrupted aspects of maturation, including transverse-tubule formation, cellular hypertrophy and fetal/adult isoform switching, whereas deletion of NAE1 in over 80% CMs led to rapid development of cardiomyopathy and heart failure. Transcriptome analysis demonstrated an association of metabolic derangement with immature cardiomyocyte signature. Biochemical, ultrastructural and metabolomics analyses confirmed downregulation of fatty acid and oxidative phosphorylation genes, deficits in fatty acid utilization, mitochondrial dysfunction, and significantly altered metabolic profiles in NAE1-deficient hearts or MLN4924-treated neonatal CMs. Mechanistically, we found that HIF1α, a transcription factor known to promote glycolysis and suppress oxidative metabolism, is a putative NEDD8 target. Inhibition of neddylation resulted in HIF1α accumulation and activation, which contributed to diminished fatty acid utilization. Taken together, we conclude that neddylation plays a crucial role in CM maturation and postnatal cardiac development through sustaining the glycolytic to oxidative metabolic switch in perinatal hearts.

Dataset Information

Transcription profiling of mouse fetal heart from wild type and Estrogen-related Receptor gamma (ERRg) knockout strains

Publications

ERRgamma directs and maintains the transition to oxidative metabolism in the postnatal heart.

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