MYC deregulates TET1 and TET2 expression to control global DNA (hydroxy)methylation and gene expression to maintain a neoplastic phenotype in T-ALL

Poole, Candace J.; Lodh, Atul; Choi, Jeong Hyeon; Riggelen, Jan van

doi:10.1186/s13072-019-0278-5

Cited by 30 publications

(33 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The average reads was 35,871,134.2 and 88.9% of the clean reads were aligned. According to a previously published method ( 28 ), the transcript abundances were estimated with StringTie v1.3.3 ( ), and the number of identified genes and transcripts per group was calculated based on the mean of fragments per kilobase of exon model million reads mapped (FPKM) in each group, and the transcripts with FPKM ≥0.5 were retained. The ballgown R package v 3.5.0 ( ) was used to analyse the differentially expressed genes (DEGs) and transcripts by comparing the NPRA −/− group to the NPRA +/+ group.…”

Section: Methodsmentioning

confidence: 99%

Cardiac‑specific deletion of natriuretic peptide receptor A induces differential myocardial expression of circular RNA and mRNA molecules involved in metabolism in mice

Chen¹,

Pan

Shen³

et al. 2020

Mol Med Rep

View full text Add to dashboard Cite

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are important biological markers and regulators of cardiac function. The natriuretic peptide receptor A (NPRA), also known as NPR1 or guanylyl cyclase A, binds ANP and BNP to initiate transmembrane signal transduction by elevating the intracellular levels of cyclic guanosine monophosphate. However, the effects and mechanisms downstream of NPRA are largely unknown. The aim of the present study was to evaluate the changes in the global pattern of mRNA and circular RNA (circRNA) expression in NPRA −/− and NPRA +/+ myocardium. Differentially expressed mRNA molecules were characterised using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis and were found to be primarily related to metabolic processes. Moreover, circRNA expression was also examined, and a possible competing endogenous RNA network consisting of circRNA, microRNA (miRNA), and mRNA molecules was constructed. The results of this study indicated that NPRA may play a role in cardiac metabolism, which could be mediated by circRNA through endogenous competition mechanisms. These findings may provide insight into future characterisation of various ceRNA network pathways.

show abstract

Section: Methodsmentioning

confidence: 99%

Cardiac‑specific deletion of natriuretic peptide receptor A induces differential myocardial expression of circular RNA and mRNA molecules involved in metabolism in mice

Chen¹,

Pan

Shen³

et al. 2020

Mol Med Rep

View full text Add to dashboard Cite

show abstract

“…Furthermore, our data and re-analysis of publically available cDNA microarray and RNA-seq data sets indicated that TET1 is overexpressed in T-ALL patients compared to healthy bone marrow (BM) derived CD34 + hematopoietic stem progenitors (HSPCs), BM derived CD3 + T-cells and naïve T-cells ( Fig. S1D-E) 29,36 . Furthermore, western blots confirmed that TET1 protein is overexpressed in T-ALL cell lines compared to CD3 + Tcells ( Fig.…”

Section: Tet1 Is Highly Expressed In Majority Of T-all Patientsmentioning

confidence: 85%

TET1 promotes growth of T-cell acute lymphoblastic leukemia and can be antagonized via PARP inhibition

et al. 2020

View full text Add to dashboard Cite

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer characterized by skewed epigenetic patterns, raising the possibility of therapeutically targeting epigenetic factors in this disease. Here we report that among different cancer types, epigenetic factor TET1 is highly expressed in TALL and is crucial for human TALL cell growth in vivo. Tet1 knockout mice and knockdown in human T-cells did not perturb normal T-cell proliferation, indicating that TET1 expression is dispensable for normal T-cell growth. The promotion of leukemic growth by TET1 was depending on its catalytic property to maintain global 5hydroxymethylcytosine (5hmC) marks, thereby regulating cell cycle, DNA repair genes and TALL associated oncogenes. Furthermore, overexpression of the Tet1 catalytic domain was sufficient to augment global 5hmC levels and leukemic growth of TALL cells in vivo. We demonstrate that PARP enzymes, which are highly expressed in TALL patients, participate in establishing H3K4me3 marks at the TET1 promoter and that PARP1 interacts with the TET1 protein. Importantly, the growth related role of TET1 in TALL could be antagonized by the clinically approved PARP inhibitor Olaparib, which abrogated TET1 expression, induced loss of 5hmC marks and antagonized leukemic growth of TALL cells, opening a therapeutic avenue for this disease. 10 transplantation (Fig. S2H). Moreover, in a published microarray analysis of TALL cell lines transplanted into xenografts, a similar increase in TET1 expression was observed (Fig. S2I), suggesting that high TET1 expression is associated with leukemic growth in vivo. Indeed, forced expression of Tet1-CD in TALL cell lines significantly augmented leukemic growth in vitro and in vivo (Fig. 3D-E). These data clearly suggest that the growth-promoting role of TET1 in TALL is at least partly dependent on its enzymatic activity. TET1 depletion induces loss of 5hmC marks at promoters and gene bodies of genes involved in cell cycle, DNA repair and NOTCH pathway Next we analyzed 5hmC levels in TALL cells via Intracellular fluorescence (IF) in our knockdown, rescue and overexpression experiments. IF-flow cytometry for 5hmC marks in TET1 depleted JURKAT cells, primary TALL patients and TET1 knockout bulk TALL cell lines revealed a significant decrease in global 5hmC levels (Fig. 4A-B and Fig. S3A-B) and increase in 5mC levels (Fig. S3C). Conversely, overexpression of Tet1-CD in TET1 depleted cells or wild type TALL cells induced a global increase in 5hmC levels (Fig. 4C-D). Furthermore, we performed hydroxymethylated DNA immunoprecipitation (hMeDIP)-seq in TET1 depleted JURKAT cells. In hMeDIP-seq, TET1 depletion resulted in more than a 59% reduction of global 5hmC enrichment at the promoter (-5kbTSS), gene body (GB) and intergenic regions compared to scrambled control (referred to as TET1 dependent 5hmC or T1-5hmC regions from here) (Fig. 4E-F). In detail, a total of 2,404 and 6,115 5hmC enriched promoters and GB were observed in the scrambled arm, respectively, out of which more th...

show abstract

“…Another study has shown that TET1 and TET2 enzymes have distinct functions in T-ALL development; TET1 acts as an oncogene in T-ALL, while TET2 is tumor suppressing [ 58 ]. Both have MYC binding sites and are regulated by this key oncogene.…”

Section: Dna Methylation In Normal Hematopoiesis and T-cell Develomentioning

confidence: 99%

“…Aberrantly expressed MYC, acting as a transcriptional activator (in case of TET1 ) and a repressor (in case of TET2 ), deregulates TETs in T-ALL, causing global methylation and hydroxymethylation abnormalities. In all analyzed T-ALL primary samples and cell lines, TET1 was overexpressed, while TET2 was downregulated [ 58 ]. After MYC inactivation in T-ALL mouse model, the opposite pattern was observed.…”

Section: Dna Methylation In Normal Hematopoiesis and T-cell Develomentioning

confidence: 99%

See 1 more Smart Citation

DNA Methylation in T-Cell Acute Lymphoblastic Leukemia: In Search for Clinical and Biological Meaning

Maćkowska

Drobna-Śledzińska

Witt

et al. 2021

IJMS

View full text Add to dashboard Cite

Distinct DNA methylation signatures, related to different prognosis, have been observed across many cancers, including T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological neoplasm. By global methylation analysis, two major phenotypes might be observed in T-ALL: hypermethylation related to better outcome and hypomethylation, which is a candidate marker of poor prognosis. Moreover, DNA methylation holds more than a clinical meaning. It reflects the replicative history of leukemic cells and most likely different mechanisms underlying leukemia development in these T-ALL subtypes. The elucidation of the mechanisms and aberrations specific to (epi-)genomic subtypes might pave the way towards predictive diagnostics and precision medicine in T-ALL. We present the current state of knowledge on the role of DNA methylation in T-ALL. We describe the involvement of DNA methylation in normal hematopoiesis and T-cell development, focusing on epigenetic aberrations contributing to this leukemia. We further review the research investigating distinct methylation phenotypes in T-ALL, related to different outcomes, pointing to the most recent research aimed to unravel the biological mechanisms behind differential methylation. We highlight how technological advancements facilitated broadening the perspective of the investigation into DNA methylation and how this has changed our understanding of the roles of this epigenetic modification in T-ALL.

show abstract

MYC deregulates TET1 and TET2 expression to control global DNA (hydroxy)methylation and gene expression to maintain a neoplastic phenotype in T-ALL

Cited by 30 publications

References 63 publications

Cardiac‑specific deletion of natriuretic peptide receptor A induces differential myocardial expression of circular RNA and mRNA molecules involved in metabolism in mice

Cardiac‑specific deletion of natriuretic peptide receptor A induces differential myocardial expression of circular RNA and mRNA molecules involved in metabolism in mice

TET1 promotes growth of T-cell acute lymphoblastic leukemia and can be antagonized via PARP inhibition

DNA Methylation in T-Cell Acute Lymphoblastic Leukemia: In Search for Clinical and Biological Meaning

Contact Info

Product

Resources

About