Histone Methyl Transferases and Demethylases; Can They Link Metabolism and Transcription?

Teperino, Raffaele; Schoonjans, Kristina; Auwerx, Johan

doi:10.1016/j.cmet.2010.09.004

Cited by 241 publications

(205 citation statements)

References 66 publications

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“…A growing body of evidence indicates the existence of an intimate link between the metabolic status and epigenetic regulation of cells (1,2). This is exemplified by the fact that a variety of small molecules involved in intercellular metabolism, including adenosine triphosphate, S-adenosylmethionine, nicotinamide adenine dinucleotide, flavin adenine dinucleotide, folate, acetyl coenzyme A, α-ketoglutarate and iron, are essential for the proper maintenance of the cellular epigenome.…”

Section: Introductionmentioning

confidence: 99%

Modulation of intracellular iron metabolism by iron chelation affects chromatin remodeling proteins and corresponding epigenetic modifications in breast cancer cells and increases their sensitivity to chemotherapeutic agents

Pogribny

Tryndyak

Pogribna

et al. 2013

International Journal of Oncology

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Abstract. Iron plays a vital role in the normal functioning of cells via the regulation of essential cellular metabolic reactions, including several DNA and histone-modifying proteins. The metabolic status of iron and the regulation of epige netic mechanisms are well-balanced and tightly controlled in normal cells; however, in cancer cells these processes are profoundly disturbed. Cancer-related abnormalities in iron metabolism have been corrected through the use of iron-chelating agents, which cause an inhibition of DNA synthesis, G 1 -S phase arrest, an inhibition of epithelial-to-mesenchymal transition, and the activation of apoptosis. In the present study, we show that, in addition to these well-studied molecular mechanisms, the treatment of wild-type TP53 MCF-7 and mutant TP53 MDA-MB-231 human breast cancer cells with desferrioxamine (DFO), a model iron chelator, causes significant epigenetic alterations at the global and gene-specific levels. Specifically, DFO treatment decreased the protein levels of the histone H3 lysine 9 demethylase, Jumonji domain-containing protein 2A (JMJD2A), in the MCF-7 and MDA-MB-231 cells and down-regulated the levels of the histone H3 lysine 4 demethylase, lysine-specific demethylase 1 (LSD1), in the MDA-MB-231 cells. These changes were accompanied by alterations in corresponding metabolically sensitive histone marks. Additionally, we demonstrate that DFO treatment activates apoptotic programs in MCF-7 and MDA-MB-231 cancer cells and enhances their sensitivity to the chemotherapeutic agents, doxorubicin and cisplatin; however, the mechanisms underlying this activation differ. The induction of apoptosis in wild-type TP53 MCF-7 cells was p53-dependent, triggered mainly by the down-regulation of the JMJD2A histone demethylase, while in mutant TP53 MDA-MB-231 cells, the activation of the p53-independent apoptotic program was driven predominantly by the epigenetic up-regulation of p21. IntroductionA growing body of evidence indicates the existence of an intimate link between the metabolic status and epigenetic regulation of cells (1,2). This is exemplified by the fact that a variety of small molecules involved in intercellular metabolism, including adenosine triphosphate, S-adenosylmethionine, nicotinamide adenine dinucleotide, flavin adenine dinucleotide, folate, acetyl coenzyme A, α-ketoglutarate and iron, are essential for the proper maintenance of the cellular epigenome.Iron is an essential trace element for normal cellular function. In addition to its significance in controlling a variety of cellular processes, including proliferation, DNA synthesis and repair, and mitochondrial electron transport, which are essential for the accurate maintenance of normal cellular homeostasis, iron plays a key regulatory role in the functioning of DNA and histone-modifying proteins (3,4). Specifically, the Jumonji domain-containing histone demethylase (JHDM) family, which catalyzes the demethylation of tri-and dimethylated lysine 9 and lysine 36 residues in histone H3 (5,6) and ten-eleven tra...

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Section: Introductionmentioning

confidence: 99%

Modulation of intracellular iron metabolism by iron chelation affects chromatin remodeling proteins and corresponding epigenetic modifications in breast cancer cells and increases their sensitivity to chemotherapeutic agents

Pogribny

Tryndyak

Pogribna

et al. 2013

International Journal of Oncology

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“…These functions are prominent features in proteins that mediate diverse protein-protein interactions and coordinate downstream events, including ubiquitination and histone methylation (45,46). Histone methylation is a reversible process catalyzed by specific and general histone methyltransferases and demethylases, which in turn rely on metabolic coenzymes and respond to changes in energy supply and metabolic status (47). The results of the present study demonstrated that the genome-wide changes in T2D were directly associated with the specific histone modifications in the process of histone methylation (48).…”

Section: Discussionmentioning

confidence: 99%

Genome-scale transcriptional analysis reveals key genes associated with the development of type II diabetes in mice

Zhang

Han

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Diabetes mellitus is one of the primary diseases that pose a threat to human health. The focus of the present study is type II diabetes (T2D), which is caused by obesity and is the most prevalent type of diabetes. However, genome-scale transcriptional analysis of diabetic liver in the development process of T2D is yet to be further elucidated. Microassays were performed on liver tissue samples from three-, six-and nine-week-old db/db mice with diabetes and db/m mice to investigate differentially expressed mRNA. Based on the results of genome-scale transcriptional analysis, five genes were screened in the present study: chromobox 8 (CBX8), de-etiolated homolog 1 and damage specific DNA binding protein 1 associated 1 (DDA1), Phosphoinositide-3-kinase regulatory subunit 6 (PIK3R6), WD repeat domain 41 (WDR41) and Glycine Amidinotransferase (GATM). At three weeks of age, no significant differences in levels or ratios of expression were observed. However, at six and nine weeks, expression of CBX8, DDA1, PIK3R6 and WDR41 was significantly upregulated (P<0.05) in the db/db model group compared with the control group, whereas GATM expression was significantly downregulated (P<0.05). These results suggest that T2D-related differential expression of genes becomes more marked with age, which was confirmed via reverse transcription-quantitative polymerase chain reaction. Genome-scale transcriptional analysis in diabetic mice provided a novel insight into the molecular. events associated with the role of mRNAs in T2D development, with specific emphasis upon CBX8, DDA1, PIK3R6, GATM and WDR41. The results of the present study may provide rationale for the investigation of the target genes of these mRNAs in future studies.

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“…In animals the inhibition of endogenous HDAC-II has primarily caused cardiac myocyte hypertrophy and also induced modest cell death [22]. In contrast, inhibition of class I HDACs presented anti-hypertrophic effect [25]. Moreover, induced expression of class II HDAC in cardiomyocytes mimics hypertrophic growth in an Akt-dependent manner [26].…”

Section: Short Communicationmentioning

confidence: 99%

Epigenetic Modifications the Development of Different Heart Failure Phenotypes

Berezin¹

2016

J Data Mining Genomics Proteomics

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Heart failure (HF) remains a leading cause of death in patient population with known cardiovascular disease. Within last two decades there are evidences regarding decline to determine newel cases with HF with reduced ejection fraction (HFrEF) in developed countries, whereas the frequency of newly-diagnosed HF with preserved ejection fraction (HFpEF) exhibits dramatically rise. Epigenetic modification is considered a modification of the non-DNA sequences related heritable changes in gene expression of target cells. Epigenetic modifications affect several molecular mechanisms, i.e., DNA methylation and deactylation, ATP-dependent chromatin remodeling, histone modifications, and microRNA regulation. The short commentary is clarified the implication of epigenetic modifications in development of different HF phenotypes.Keywords: Heart failure; Heart failure with preserved ejection fraction; Heart failure with reduced ejection fraction; Epigenetics Short CommunicationHeart failure (HF) is a sufficient medical problem and social burden that associates with increased morbidity/mortality rate and disability rate in the developed countries [1]. Within last decades there is progressively decrease of prevalence of HF with reduced left ventricular ejection fraction (HFrEF) [2]. In opposite, the frequency of newly-diagnosed HF with preserved left ventricular ejection fraction (HFpEF) appears to be raised [3]. These changes in presentation of HF phenotypes might relate to advance in contemporary of HF medical care [4], impact of age-related comorbidities and socioeconomic status [5][6][7][8]. Despite the implementation in routine clinical practice modern pharmacological strategy and none-drug therapy including implanted devices for mechanical support and pacing [8][9][10], the clinical outcomes in subjects with HFrEF and HFpEF remain similar [11].

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Histone Methyl Transferases and Demethylases; Can They Link Metabolism and Transcription?

Cited by 241 publications

References 66 publications

Modulation of intracellular iron metabolism by iron chelation affects chromatin remodeling proteins and corresponding epigenetic modifications in breast cancer cells and increases their sensitivity to chemotherapeutic agents

Modulation of intracellular iron metabolism by iron chelation affects chromatin remodeling proteins and corresponding epigenetic modifications in breast cancer cells and increases their sensitivity to chemotherapeutic agents

Genome-scale transcriptional analysis reveals key genes associated with the development of type II diabetes in mice

Epigenetic Modifications the Development of Different Heart Failure Phenotypes

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