How Epigenetic Modifications Drive the Expression and Mediate the Action of PGC-1α in the Regulation of Metabolism

Krämer, Anne I.; Handschin, Christoph

doi:10.3390/ijms20215449

Cited by 21 publications

(10 citation statements)

References 84 publications

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“…T he transcriptional peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a canonical regulatory component of physiological processes such as cold, fasting, and exercise (1)(2)(3)(4). PGC-1α is itself regulated at multiple levels including transcription, translation, and posttranslation (5)(6)(7)(8)(9). As a transcriptional coactivator, PGC-1α increases expression of genes associated with energy metabolism and mitochondrial biogenesis through binding to transcription factors (10)(11)(12).…”

mentioning

confidence: 99%

Transcriptome-wide analysis of PGC-1α–binding RNAs identifies genes linked to glucagon metabolic action

Tavares

Aigner

Sharabi

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a transcriptional coactivator that controls expression of metabolic/energetic genes, programming cellular responses to nutrient and environmental adaptations such as fasting, cold, or exercise. Unlike other coactivators, PGC-1α contains protein domains involved in RNA regulation such as serine/arginine (SR) and RNA recognition motifs (RRMs). However, the RNA targets of PGC-1α and how they pertain to metabolism are unknown. To address this, we performed enhanced ultraviolet (UV) cross-linking and immunoprecipitation followed by sequencing (eCLIP-seq) in primary hepatocytes induced with glucagon. A large fraction of RNAs bound to PGC-1α were intronic sequences of genes involved in transcriptional, signaling, or metabolic function linked to glucagon and fasting responses, but were not the canonical direct transcriptional PGC-1α targets such as OXPHOS or gluconeogenic genes. Among the top-scoring RNA sequences bound to PGC-1α were Foxo1, Camk1δ, Per1, Klf15, Pln4, Cluh, Trpc5, Gfra1, and Slc25a25. PGC-1α depletion decreased a fraction of these glucagon-induced messenger RNA (mRNA) transcript levels. Importantly, knockdown of several of these genes affected glucagon-dependent glucose production, a PGC-1α–regulated metabolic pathway. These studies show that PGC-1α binds to intronic RNA sequences, some of them controlling transcript levels associated with glucagon action.

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mentioning

confidence: 99%

Transcriptome-wide analysis of PGC-1α–binding RNAs identifies genes linked to glucagon metabolic action

Tavares

Aigner

Sharabi

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Earlier studies have shown that one of the consequential effects of elevated DNMT1 and high DNA methylation may be the deterioration of mitochondrial function, as few studies indicate that DNA methylation can control the expression of nuclear-encoded mitochondrial genes like PGC1α [ 17 ], TFAM [ 18 ], and POLGA [ 19 ]. These genes are critical for the mitochondrial bio-energetic functions, transcription, translation, and replication of cellular mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Diabetic Hearts Exhibit Global DNA Hypermethylation That Alter the Mitochondrial Functional Genes to Enhance the Sensitivity of the Heart to Ischemia Reperfusion Injury

et al. 2022

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A recent study has shown that DNA hypermethylation can promote ischemia reperfusion (I/R) injury by regulating the mitochondrial function. Diabetes mellitus (DM) is reported to induce DNA hypermethylation, but whether this prior DNA methylation in DM I/R heart inflicts a beneficial or detrimental effect is not known and is addressed in this study. DM was induced in 6-week-old male Wistar rats with streptozotocin (65 mg/kg b.wt). After 24 weeks on a normal diet, I/R was induced in rat heart using a Langendorff perfusion system and analyzed the myocardium for different parameters to measure hemodynamics, infarct size, DNA methylation and mitochondrial function. Diabetic heart exhibited DNA hypermethylation of 39% compared to the control, along with DNMT expression elevated by 41%. I/R induction in diabetic heart promoted further DNA hypermethylation (24%) with aggravated infarct size (21%) and reduced the cardiac rate pressure product (43%) from I/R heart. Importantly, diabetic I/R hearts also experienced a decline in the mitochondrial copy number (60%); downregulation in the expression of mitochondrial bioenergetics (ND1, ND2, ND3, ND4, ND5, ND6) and mitofusion (MFN1, MFN2) genes and the upregulation of mitophagy (PINK, PARKIN, OPTN) and mitofission (MFF, DNM1, FIS1) genes that reduce the dp/dt contribute to the contractile dysfunction in DM I/R hearts. Besides, a negative correlation was obtained between mitochondrial PGC1α, POLGA, TFAM genes and DNA hypermethylation in DM I/R hearts. Based on the above data, the elevated global DNA methylation level in diabetic I/R rat hearts deteriorated the mitochondrial function by downregulating the expression of POLGA, TFAM and PGC1α genes and negatively contributed to I/R-associated increased infarct size and altered hemodynamics.

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“…If this were not the case and tissue-specific posttranscriptional control had been superimposed on broad transcription profiles, we would not have seen the many examples of tissue-specific promoter/enhancer/open chromatin/DNA methylation profiles corresponding to expression profiles. Reports of epigenetic changes correlated with disease or altered physiological states usually focus on changes at promoters, which are easier to locate on the genome (e.g., [ 24 , 61 , 62 , 63 , 64 ]), although there are noteworthy exceptions (e.g., [ 65 ]). Our study reinforces the importance of testing for disease- and physiology-linked changes in chromatin and DNA epigenetics also at enhancers, which can show more extensive tissue-specific differences correlated with expression than do promoters ( Figure 3 , Figure 6 , Figures S3, S4 and S6 ).…”

Section: Discussionmentioning

confidence: 99%

Epigenetics of Mitochondria-Associated Genes in Striated Muscle

2021

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Striated muscle has especially large energy demands. We identified 97 genes preferentially expressed in skeletal muscle and heart, but not in aorta, and found significant enrichment for mitochondrial associations among them. We compared the epigenomic and transcriptomic profiles of the 27 genes associated with striated muscle and mitochondria. Many showed strong correlations between their tissue-specific transcription levels, and their tissue-specific promoter, enhancer, or open chromatin as well as their DNA hypomethylation. Their striated muscle-specific enhancer chromatin was inside, upstream, or downstream of the gene, throughout much of the gene as a super-enhancer (CKMT2, SLC25A4, and ACO2), or even overlapping a neighboring gene (COX6A2, COX7A1, and COQ10A). Surprisingly, the 3′ end of the 1.38 Mb PRKN (PARK2) gene (involved in mitophagy and linked to juvenile Parkinson’s disease) displayed skeletal muscle/myoblast-specific enhancer chromatin, a myoblast-specific antisense RNA, as well as brain-specific enhancer chromatin. We also found novel tissue-specific RNAs in brain and embryonic stem cells within PPARGC1A (PGC-1α), which encodes a master transcriptional coregulator for mitochondrial formation and metabolism. The tissue specificity of this gene’s four alternative promoters, including a muscle-associated promoter, correlated with nearby enhancer chromatin and open chromatin. Our in-depth epigenetic examination of these genes revealed previously undescribed tissue-specific enhancer chromatin, intragenic promoters, regions of DNA hypomethylation, and intragenic noncoding RNAs that give new insights into transcription control for this medically important set of genes.

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How Epigenetic Modifications Drive the Expression and Mediate the Action of PGC-1α in the Regulation of Metabolism

Cited by 21 publications

References 84 publications

Transcriptome-wide analysis of PGC-1α–binding RNAs identifies genes linked to glucagon metabolic action

Transcriptome-wide analysis of PGC-1α–binding RNAs identifies genes linked to glucagon metabolic action

Diabetic Hearts Exhibit Global DNA Hypermethylation That Alter the Mitochondrial Functional Genes to Enhance the Sensitivity of the Heart to Ischemia Reperfusion Injury

Epigenetics of Mitochondria-Associated Genes in Striated Muscle

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