TETology: Epigenetic Mastermind in Action

Seethy, Ashikh; Pethusamy, Karthikeyan; Chattopadhyay, Indranil; Sah, Ramkishor; Chopra, Anita; Dhar, Ruby; Karmakar, Subhradip

doi:10.1007/s12010-021-03537-5

Cited by 24 publications

(14 citation statements)

References 171 publications

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“…Another 2OGDD enzymes involved in kidney diseases is the ten-eleven translocation methyl-cytosine dioxygenase (TET)1-3, which catalyzes the conversion of 5-methyl cytosine (5mC) to 5-hydroxymethyl cytosine (5hmC), an epigenetic mark on DNA associated with active transcription [ 106 ]. In tissue derived from CKD patients, TET1-3 levels are increased; however, their activity is decreased [ 107 ], indicating an imbalance in 5mC/5hmC.…”

Section: Alpha-ketoglutaratementioning

confidence: 99%

Involvement of Tricarboxylic Acid Cycle Metabolites in Kidney Diseases

et al. 2021

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Mitochondria are complex organelles that orchestrate several functions in the cell. The primary function recognized is energy production; however, other functions involve the communication with the rest of the cell through reactive oxygen species (ROS), calcium influx, mitochondrial DNA (mtDNA), adenosine triphosphate (ATP) levels, cytochrome c release, and also through tricarboxylic acid (TCA) metabolites. Kidney function highly depends on mitochondria; hence mitochondrial dysfunction is associated with kidney diseases. In addition to oxidative phosphorylation impairment, other mitochondrial abnormalities have been described in kidney diseases, such as induction of mitophagy, intrinsic pathway of apoptosis, and releasing molecules to communicate to the rest of the cell. The TCA cycle is a metabolic pathway whose primary function is to generate electrons to feed the electron transport system (ETS) to drives energy production. However, TCA cycle metabolites can also release from mitochondria or produced in the cytosol to exert different functions and modify cell behavior. Here we review the involvement of some of the functions of TCA metabolites in kidney diseases.

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Section: Alpha-ketoglutaratementioning

confidence: 99%

Involvement of Tricarboxylic Acid Cycle Metabolites in Kidney Diseases

et al. 2021

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“…TET2 and the highly homologous TET1 and TET3 genes are the only known DNA dioxygenases catalyzing the conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC). 1 Because of the inability of methyltransferases to recognize 5-hmC during DNA replication, TET enzymes can be considered as demethylases. Hematopoietic stem and progenitor cells (HSPCs) express ubiquitous levels of TET2 and TET3 while expressing very low levels of TET1.…”

Section: Introductionmentioning

confidence: 99%

TET2 mutations as a part of DNA dioxygenase deficiency in myelodysplastic syndromes

et al. 2022

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Decrease in DNA dioxygease activity generated by TET2 gene family is crucial in myelodysplastic syndromes (MDS). The general down-regulation of 5-hydroxymethylcytosine (5-hmC) argues for a role of DNA demethylation in MDS beyond TET2 mutations, which albeit frequent, do not convey any prognostic significance. We investigated TETs expression to identify factors which can modulate the impact of mutations and thus 5-hmC levels on clinical phenotypes and prognosis of MDS patients. DNA/RNA-sequencing and 5-hmC data were collected from 1,665 patients with MDS and 91 controls. Irrespective of mutations, a significant fraction of MDS patients exhibited lower TET2 expression, while 5-hmC levels were not uniformly decreased. In searching for factors explaining compensatory mechanisms, we discovered that TET3 was up-regulated in MDS and inversely correlated with TET2 expression in wild-type cases. While TET2 was reduced across all age-groups, TET3 levels were increased in a likely feedback mechanism induced by TET2 dysfunction. This inverse relationship of TET2 and TET3 expression also corresponded to the expression of L-2-hydroxyglutarate dehydrogenase, involved in agonist/antagonist substrate metabolism. Importantly, elevated TET3 levels influenced the clinical phenotype of TET2-deficiency whereby the lack of compensation by TET3 (low TET3 expression) was associated with poor outcomes of TET2 mutant carriers.

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“…It is well known that aside genetic factors also epigenetic factors can contribute to the initiation and progression of PrCa [ 34 ]. TET2 is an enzyme involved in DNA demethylation, and it has been shown to be an important player during tumorigenesis [ 35 ]. TET2 has been shown to be able to bind to the androgen receptor and modulate its signalling pathway.…”

Section: Discussionmentioning

confidence: 99%

Unravelling genetic variants of a swedish family with high risk of prostate cancer

Barilla

Lindblom

Helgadottir

2022

Hered Cancer Clin Pract

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Background Prostate cancer is the most prevalent cancer in men worldwide. It is a polygenic disease with a substantial proportion of heritability. Identification of novel candidate biomarkers is crucial for clinical cancer prevention and the development of therapeutic strategies. Here, we describe the analysis of rare and common genetic variants that can predispose to the development of prostate cancer. Methods Whole-genome sequencing was performed on germline DNA of five Swedish siblings which were diagnosed with prostate cancer. The high-risk variants were identified setting the minor allele frequency < 0.01, CADD > 10 and if tested in PRACTICAL, OR > 1.5, while the low-risk variants were identified minor allele frequency > 0.01, CADD > 10 and if tested in PRACTICAL, OR > 1.1. Results We identified 38 candidate high-risk gene variants and 332 candidate low-risk gene variants, where 2 and 14 variants were in coding regions, respectively, that were shared by the brothers with prostate cancer. Conclusions This study expanded the knowledge of potential risk factor candidates involved in hereditary and familial prostate cancer. Our findings can be beneficial when applying targeted screening in families with a high risk of developing the disease.

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TETology: Epigenetic Mastermind in Action

Cited by 24 publications

References 171 publications

Involvement of Tricarboxylic Acid Cycle Metabolites in Kidney Diseases

Involvement of Tricarboxylic Acid Cycle Metabolites in Kidney Diseases

TET2 mutations as a part of DNA dioxygenase deficiency in myelodysplastic syndromes

Unravelling genetic variants of a swedish family with high risk of prostate cancer

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