AMPK: An Epigenetic Landscape Modulator

Gongol, Brendan; Sari, Indah Komala; Bryant, Tiffany; Rosete, Geraldine; Marin, Traci

doi:10.3390/ijms19103238

Cited by 45 publications

(36 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AMPK is known to influence chromatin accessibility e.g., via modulated histone acetylation (e.g., Gongol et al, 2018). Notably, AMPK −/− cells displayed higher global acetylation of selected lysine residues on histone 3 (K14,18, 27, and 56) ( Supplementary Figure 3), possibly causing a dilution effect of Nrf2 by more accessible binding sites in the knockout cells, as previously outlined (Brewster et al, 2014;Rydenfelt et al, 2014).…”

Section: Wt and Ampk−/− Cells Do Not Markedly Differ In The Local Chrsupporting

confidence: 53%

See 1 more Smart Citation

AMPK Enhances Transcription of Selected Nrf2 Target Genes via Negative Regulation of Bach1

Fischhuber

Matzinger

Heiß

2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

5-AMP-activated protein kinase (AMPK) and the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) are main players in the cellular adaptive response to metabolic and oxidative/xenobiotic stress, respectively. AMPK does not only balance the rate of fuel catabolism versus anabolism but also emerges as regulator of gene expression. We here examined the influence of AMPK on Nrf2-dependent gene transcription and the potential interplay of the two cellular stress hubs. Using gene expression analyses in wt and AMPKα1 −/− or Nrf2 −/− mouse embryonal fibroblasts, we could show that AMPK only affected a portion of the entire of Nrf2-dependent transcriptome upon exposure to the Nrf2 activator sulforaphane (Sfn). Focusing on selected genes with positive regulation by Nrf2 and either positive or no further regulation by AMPK, we revealed that altered Nrf2 levels could not account for the distinct extent of transactivation of certain Nrf2 targets in wt and AMPK −/− cells (assessed by immunoblot). FAIRE-qPCR largely excluded distinct chromatin accessibility of selected Nrf2-responsive antioxidant response elements (ARE) within the regulatory gene regions in wt and AMPK−/− cells. However, expression analyses and ChIP-qPCR showed that in AMPK−/− cells, levels of BTB and CNC homology 1 (Bach1), a competitor of Nrf2 for ARE sites with predominant repressor function, were higher, and Bach1 also bound to a greater relative extent to the examined ARE sites when compared to Nrf2. The negative influence of AMPK on Bach1 was confirmed by pharmacological and genetic approaches and occurred at the level of mRNA synthesis. Overall, the observed AMPK-mediated boost in transactivation of a subset of Nrf2 target genes involves downregulation of Bach1 and subsequent favored binding of activating Nrf2 over repressing Bach1 to the examined ARE sites.

show abstract

Section: Wt and Ampk−/− Cells Do Not Markedly Differ In The Local Chrsupporting

confidence: 53%

“…acetylation (Gongol et al, 2018) and an increased global histone acetylation in the used AMPK −/− cells compared to wt cells. Notably, examined ARE sites appeared to be within relatively loosely packed chromatin throughout all tested conditions.…”

Section: Discussionmentioning

confidence: 94%

AMPK Enhances Transcription of Selected Nrf2 Target Genes via Negative Regulation of Bach1

Fischhuber

Matzinger

Heiß

2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…These genes can also be found to be methylated, with PGC1a modifications affecting mitochondrial density in type 2 diabetic patients [ 51 , 52 ], and NRF1 methylation causing TFAM (mitochondrial transcription factor A) silencing and a reduction in mitochondrial biogenesis [ 53 ]. In fact, methylation of PGC1a can additionally be modulated by nuclear DNMT3 [ 52 ] or DNMT1, the latter of which can be inhibited by AMPK (AMP-activated protein kinase) phosphorylation [ 54 ]. These studies raise the question of whether differential methylation of nuclear genes controlling the expression and activity of DNMT1 may also indirectly lead to changes in mtDNA methylation.…”

Section: Is Mitochondrial Dna Methylated?mentioning

confidence: 99%

“…While it presents an inhibitory role towards DNMT1, it can also have a stimulatory effect on DNMT3s. The latter takes place as AMPK either transactivates let-7 microRNA which leads to an increase in the SAM/SAH ratio, or it activates serine hydroxymethyltransferase 2 (SHMT2) which converts serine to glycine in the mitochondria, facilitating production of SAM [ 54 ] (Fig. 3 ).…”

Section: Effects Of Mitochondria On Nuclear Dna Methylationmentioning

confidence: 99%

Mitochondrial metabolism and DNA methylation: a review of the interaction between two genomes

Lopes

2020

Clin Epigenet

View full text Add to dashboard Cite

Mitochondria are controlled by the coordination of two genomes: the mitochondrial and the nuclear DNA. As such, variations in nuclear gene expression as a consequence of mutations and epigenetic modifications can affect mitochondrial functionality. Conversely, the opposite could also be true. However, the relationship between mitochondrial dysfunction and epigenetics, such as nuclear DNA methylation, remains largely unexplored. Mitochondria function as central metabolic hubs controlling some of the main substrates involved in nuclear DNA methylation, via the one carbon metabolism, the tricarboxylic acid cycle and the methionine pathway. Here, we review key findings and highlight new areas of focus, with the ultimate goal of getting one step closer to understanding the genomic effects of mitochondrial dysfunction on nuclear epigenetic landscapes.

show abstract

“…Once activated, AMPK phosphorylates several downstream targets [6,[8][9][10], thereby inhibiting energy consumption and promoting energy production to ensure cellular survival [7]. Besides its role as a central hub in cellular energy utilization, AMPK is also involved in a number of other important biological functions (for review see Kahn et al, [11]), including the recently described regulation of the epigenetic pathways ( Figure 1) [11,12]. The first hints of AMPK's cardiovascular influence were shown in 1999 by Chen et al who reported direct phosphorylation sites on endothelial NO-Synthase enzyme in endothelial cells and myocytes [13].…”

Section: Introductionmentioning

confidence: 99%

The AMP-Activated Protein Kinase Plays a Role in Antioxidant Defense and Regulation of Vascular Inflammation

et al. 2020

View full text Add to dashboard Cite

Cardiovascular diseases represent the leading cause of global deaths and life years spent with a severe disability. Endothelial dysfunction and vascular oxidative stress are early precursors of atherosclerotic processes in the vascular wall, all of which are hallmarks in the development of cardiovascular diseases and predictors of future cardiovascular events. There is growing evidence that inflammatory processes represent a major trigger for endothelial dysfunction, vascular oxidative stress and atherosclerosis and clinical data identified inflammation as a cardiovascular risk factor on its own. AMP-activated protein kinase (AMPK) is a central enzyme of cellular energy balance and metabolism that has been shown to confer cardio-protection and antioxidant defense which thereby contributes to vascular health. Interestingly, AMPK is also redox-regulated itself. We have previously shown that AMPK largely contributes to a healthy endothelium, confers potent antioxidant effects and prevents arterial hypertension. Recently, we provided deep mechanistic insights into the role of AMPK in cardiovascular protection and redox homeostasis by studies on arterial hypertension in endothelial and myelomonocytic cell-specific AMPK knockout (Cadh5CrexAMPKfl/fl and LysMCrexAMPKfl/fl) mice. Using these cell-specific knockout mice, we revealed the potent anti-inflammatory properties of AMPK representing the molecular basis of the antihypertensive effects of AMPK. Here, we discuss our own findings in the context of literature data with respect to the anti-inflammatory and antioxidant effects of AMPK in the specific setting of arterial hypertension as well as cardiovascular diseases in general.

show abstract

AMPK: An Epigenetic Landscape Modulator

Cited by 45 publications

References 79 publications

AMPK Enhances Transcription of Selected Nrf2 Target Genes via Negative Regulation of Bach1

AMPK Enhances Transcription of Selected Nrf2 Target Genes via Negative Regulation of Bach1

Mitochondrial metabolism and DNA methylation: a review of the interaction between two genomes

The AMP-Activated Protein Kinase Plays a Role in Antioxidant Defense and Regulation of Vascular Inflammation

Contact Info

Product

Resources

About