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Epigenetic Modifications of the PGC-1? Promoter during Exercise Induced Expression in Mice.

ABSTRACT: The transcriptional coactivator, PGC-1?, is known for its role in mitochondrial biogenesis. Although originally thought to exist as a single protein isoform, recent studies have identified additional promoters which produce multiple mRNA transcripts. One of these promoters (promoter B), approximately 13.7 kb upstream of the canonical PGC-1? promoter (promoter A), yields alternative transcripts present at levels much lower than the canonical PGC-1? mRNA transcript. In skeletal muscle, exercise resulted in a substantial, rapid increase of mRNA of these alternative PGC-1? transcripts. Although the ?2-adrenergic receptor was identified as a signaling pathway that activates transcription from PGC-1? promoter B, it is not yet known what molecular changes occur to facilitate PGC-1? promoter B activation following exercise. We sought to determine whether epigenetic modifications were involved in this exercise response in mouse skeletal muscle. We found that DNA hydroxymethylation correlated to increased basal mRNA levels from PGC-1? promoter A, but that DNA methylation appeared to play no role in the exercise-induced activation of PGC-1? promoter B. The level of the activating histone mark H3K4me3 increased with exercise 2-4 fold across PGC-1? promoter B, but remained unaltered past the canonical PGC-1? transcriptional start site. Together, these data show that epigenetic modifications partially explain exercise-induced changes in the skeletal muscle mRNA levels of PGC-1? isoforms.

SUBMITTER: Lochmann TL

PROVIDER: S-EPMC4460005 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Epigenetic Modifications of the PGC-1α Promoter during Exercise Induced Expression in Mice.

Lochmann Timothy L TL Thomas Ravindar R RR Bennett James P JP Taylor Shirley M SM

PloS one 20150608 6

The transcriptional coactivator, PGC-1α, is known for its role in mitochondrial biogenesis. Although originally thought to exist as a single protein isoform, recent studies have identified additional promoters which produce multiple mRNA transcripts. One of these promoters (promoter B), approximately 13.7 kb upstream of the canonical PGC-1α promoter (promoter A), yields alternative transcripts present at levels much lower than the canonical PGC-1α mRNA transcript. In skeletal muscle, exercise re ...[more]

PMID: 26053857

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Project description:The polycomb repressor complex 2 molecule EZH2 is now known to play a role in essential cellular processes, namely, cell fate decisions, cell cycle regulation, senescence, cell differentiation, and cancer development/progression. EZH2 inhibitors have recently been developed; however, their effectiveness and underlying molecular mechanisms in many malignancies have not yet been elucidated in detail. Although the functional role of EZH2 in tumorigenesis in neuroblastoma (NB) has been investigated, mutations of EZH2 have not been reported. A Kaplan-Meier analysis on the event free survival and overall survival of NB patients indicated that the high expression of EZH2 correlated with an unfavorable prognosis. In order to elucidate the functional roles of EZH2 in NB tumorigenesis and its aggressiveness, we knocked down EZH2 in NB cell lines using lentivirus systems. The knockdown of EZH2 significantly induced NB cell differentiation, e.g., neurite extension, and the neuronal differentiation markers, NF68 and GAP43. EZH2 inhibitors also induced NB cell differentiation. We performed a comprehensive transcriptome analysis using Human Gene Expression Microarrays and found that NTRK1 (TrkA) is one of the EZH2-related suppression targets. The depletion of NTRK1 canceled EZH2 knockdown-induced NB cell differentiation. Our integrative methylome, transcriptome, and chromatin immunoprecipitation assays using NB cell lines and clinical samples clarified that the NTRK1 P1 and P2 promoter regions were regulated differently by DNA methylation and EZH2-related histone modifications. The NTRK1 transcript variants 1/2, which were regulated by EZH2-related H3K27me3 modifications at the P1 promoter region, were strongly expressed in favorable, but not unfavorable NB. The depletion and inhibition of EZH2 successfully induced NTRK1 transcripts and functional proteins. Collectively, these results indicate that EZH2 plays important roles in preventing the differentiation of NB cells and also that EZH2-related NTRK1 transcriptional regulation may be the key pathway for NB cell differentiation.

Dataset Information

Epigenetic Modifications of the PGC-1? Promoter during Exercise Induced Expression in Mice.

Publications

Epigenetic Modifications of the PGC-1α Promoter during Exercise Induced Expression in Mice.

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