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Phosphorylation of TET2 by AMPK is indispensable in myogenic differentiation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE126371 | GEO | 2019/06/06

REPOSITORIES: GEO

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Phosphorylation of TET2 by AMPK is indispensable in myogenic differentiation.

Project description:BackgroundTET-mediated oxidation of 5-mC participates in both passive and active DNA demethylation, which exerts a significant influence on diverse biological processes. Mass spectrometry has identified multiple phosphorylation sites of TET2. However, the functions of these phosphosites and their corresponding kinases are mostly unknown.ResultsHere, we showed that AMP-activated protein kinase (AMPK) phosphorylates murine TET2 at the serine residue 97 (S97), and the phosphorylation enhances TET2 stability through promoting its binding to 14-3-3β. AMPK ablation resulted in decreased global 5-hmC levels at the myotube stages, severe differentiation defects of C2C12 cells and significantly, total loss of expression of Pax7. Genome-wide analyses revealed increased DNA methylation at genic and enhancer regions of AMPK-null myoblasts and myotubes. Using CRISPR/Cas9 technology, we showed that a novel enhancer, which is hypermethylated in AMPK-null cells, regulates Pax7 expression. The phospho-mimicking mutant, TET2-S97E, could partly rescue the differentiation defect in AMPK-ablated C2C12 cells.ConclusionsTogether, our data demonstrated that AMPK is a critical regulator of myogenesis, partly through phosphorylating TET2.

| S-EPMC6547497 | biostudies-literature

Phosphorylation of TET2 by AMPK is indispensable in myogenic differentiation [MeDIP-seq]

Project description:TET-mediated oxidation of 5-mC participates in both passive and active DNA demethylation, which exerts a significant influence on diverse biological processes. Mass spectrometry has identified multiple phosphorylation sites of TET2. However, the functions of these phosphosites and their corresponding kinases are mostly unknown. Here we showed that AMP-activated protein kinase (AMPK) phosphorylates murine TET2 at the serine residue 97 (S97), enhances TET2 stability through promoting its binding to 14-3-3β. AMPK ablation resulted in decreased global 5-hmC levels at the myotube stages, severe differentiation defects of C2C12 cells and, significantly, total loss of expression of Pax7. Genome-wide analyses revealed increased DNA methylation at genic and enhancer regions of AMPK-null myoblasts and myotubes. Using CRISPR/Cas9 technology, we showed that a novel enhancer, which is hypermethylated in AMPK-null cells, regulates Pax7 expression. The phospho-mimicking mutant, TET2-S97E, could partly rescue the differentiation defect in AMPK ablated C2C12 cells. Together, our data demonstrated that AMPK is a critical regulator of myogenesis, partly through phosphorylating TET2.

2019-06-06 | GSE126369 | GEO

Phosphorylation of TET2 by AMPK is indispensable in myogenic differentiation [RNA-seq]

2019-06-06 | GSE126370 | GEO

Phosphorylation of TET2 by AMPK is indispensable in myogenic differentiation

Project description:Phosphorylation of TET2 by AMPK is indispensable in myogenic differentiation

| PRJNA521716 | ENA

Phosphorylation of TET2 by AMPK is indispensable in myogenic differentiation [RNA-seq]

Project description:Phosphorylation of TET2 by AMPK is indispensable in myogenic differentiation [RNA-seq]

| PRJNA521721 | ENA

Phosphorylation of TET2 by AMPK is indispensable in myogenic differentiation [MeDIP-seq]

Project description:Phosphorylation of TET2 by AMPK is indispensable in myogenic differentiation [MeDIP-seq]

| PRJNA521719 | ENA

TET2 and TET3 loss disrupts small intestine differentiation and homeostasis

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-05-22 | GSE200230 | GEO

The phosphorylation of FOXA1-S331 is indispensable for FOXA1-AR dependent cistrome.

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-05-01 | GSE232125 | GEO

Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer.

Project description:Diabetes is a complex metabolic syndrome that is characterized by prolonged high blood glucose levels and frequently associated with life-threatening complications1,2. Epidemiological studies have suggested that diabetes is also linked to an increased risk of cancer3-5. High glucose levels may be a prevailing factor that contributes to the link between diabetes and cancer, but little is known about the molecular basis of this link and how the high glucose state may drive genetic and/or epigenetic alterations that result in a cancer phenotype. Here we show that hyperglycaemic conditions have an adverse effect on the DNA 5-hydroxymethylome. We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo. Treatment with the anti-diabetic drug metformin protects AMPK-mediated phosphorylation of serine 99, thereby increasing TET2 stability and 5hmC levels. These findings define a novel 'phospho-switch' that regulates TET2 stability and a regulatory pathway that links glucose and AMPK to TET2 and 5hmC, which connects diabetes to cancer. Our data also unravel an epigenetic pathway by which metformin mediates tumour suppression. Thus, this study presents a new model for how a pernicious environment can directly reprogram the epigenome towards an oncogenic state, offering a potential strategy for cancer prevention and treatment.

| S-EPMC6430198 | biostudies-literature

Phosphorylation of EZH2 by AMPK Suppresses PRC2 Methyltransferase Activity and Oncogenic Function

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-12-15 | GSE97736 | GEO