scholarly journals Advances in the DNA methylation hydroxylase TET1

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Wenzheng Liu ◽  
Guanhua Wu ◽  
Fei Xiong ◽  
Yongjun Chen
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Cpg Islands ◽  
Embryonic Stem ◽  
Dna Demethylation ◽  
Research Progress ◽  
Malignant Tumours ◽  
Key Factor ◽  
Tet Protein ◽  
Genomic Methylation

Abstract Background The ten-eleven translocation 1 (TET1) protein is a 5-methylcytosine hydroxylase that belongs to the TET protein family of human α-ketoglutarate oxygenases. TET1 recognizes and binds to regions of high genomic 5′-CpG-3′ dinucleotide density, such as CpG islands, initiates the DNA demethylation program, and maintains DNA methylation and demethylation balance to maintain genomic methylation homeostasis and achieve epigenetic regulation. This article reviews the recent research progress of TET1 in the mechanism of demethylation, stem cells and immunity, various malignant tumours and other clinical diseases. Conclusion TET1 acts as a key factor mediating demethylation, the mechanism of which still remains to be investigated in detail. TET1 is also critical in maintaining the differentiation pluripotency of embryonic stem cells and plays anti- or oncogenic roles in combination with different signalling pathways in different tumours. In certain tumours, its role is still controversial. In addition, the noncatalytic activity of TET1 has gradually attracted attention and has become a new direction of research in recent years.

scholarly journals DAXX safeguards pericentromeric heterochromatin formation in embryonic stem cells

2021 ◽  
Author(s):  
Antoine Canat ◽  
Adeline Veillet ◽  
Robert Illingworth ◽  
Emmanuelle Fabre ◽  
Pierre Therizols
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Dna Damage ◽  
Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Pericentric Heterochromatin ◽  
Dna Demethylation ◽  
Pericentromeric Heterochromatin ◽  
Major Satellite ◽  
Heterochromatin Formation

AbstractDNA methylation is essential for heterochromatin formation and repression of DNA repeat transcription, both of which are essential for genome integrity. Loss of DNA methylation is associated with disease, including cancer, but is also required for development. Alternative pathways to maintain heterochromatin are thus needed to limit DNA damage accumulation. Here, we find that DAXX, an H3.3 chaperone, protects pericentromeric heterochromatin and is essential for embryonic stem cells (ESCs) maintenance in the ground-state of pluripotency. Upon DNA demethylation-mediated damage, DAXX relocalizes to pericentromeric regions, and recruits PML and SETDB1, thereby promoting heterochromatin formation. In the absence of DAXX, the 3D-architecture and physical properties of pericentric heterochromatin are disrupted, resulting in derepression of major satellite DNA. Using epigenome editing tools, we demonstrate that H3.3, and specifically H3.3K9 modification, directly contribute to maintaining pericentromeric chromatin conformation. Altogether, our data reveal that DAXX and H3.3 unite DNA damage response and heterochromatin maintenance in ESCs.

scholarly journals PROSER1 mediates TET2 O-GlcNAcylation to regulate DNA demethylation on UTX-dependent enhancers and CpG islands

2021 ◽  
Vol 5 (1) ◽  
pp. e202101228
Author(s):  
Xiaokang Wang ◽  
Wojciech Rosikiewicz ◽  
Yurii Sedkov ◽  
Tanner Martinez ◽  
Baranda S Hansen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Target Genes ◽  
Cpg Islands ◽  
Dna Demethylation ◽  
Dna Hypermethylation ◽  
Genome Wide ◽  
Associated Proteins ◽  
Tet Enzymes ◽  
Tet Protein ◽  
First Time

DNA methylation at enhancers and CpG islands usually leads to gene repression, which is counteracted by DNA demethylation through the TET protein family. However, how TET enzymes are recruited and regulated at these genomic loci is not fully understood. Here, we identify TET2, the glycosyltransferase OGT and a previously undescribed proline and serine rich protein, PROSER1 as interactors of UTX, a component of the enhancer-associated MLL3/4 complexes. We find that PROSER1 mediates the interaction between OGT and TET2, thus promoting TET2 O-GlcNAcylation and protein stability. In addition, PROSER1, UTX, TET1/2, and OGT colocalize on many genomic elements genome-wide. Loss of PROSER1 results in lower enrichment of UTX, TET1/2, and OGT at enhancers and CpG islands, with a concomitant increase in DNA methylation and transcriptional down-regulation of associated target genes and increased DNA hypermethylation encroachment at H3K4me1-predisposed CpG islands. Furthermore, we provide evidence that PROSER1 acts as a more general regulator of OGT activity by controlling O-GlcNAcylation of multiple other chromatin signaling pathways. Taken together, this study describes for the first time a regulator of TET2 O-GlcNAcylation and its implications in mediating DNA demethylation at UTX-dependent enhancers and CpG islands and supports an important role for PROSER1 in regulating the function of various chromatin-associated proteins via OGT-mediated O-GlcNAcylation.

scholarly journals Deletion of Tet proteins results in quantitative disparities during ESC differentiation partially attributable to alterations in gene expression

2019 ◽  
Author(s):  
Michael J Reimer ◽  
Kirthi Pulakanti ◽  
Linzheng Shi ◽  
Alex Abel ◽  
Mingyu Liang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Critical Role ◽  
Embryonic Stem ◽  
Dna Demethylation ◽  
Intermediate Phenotype ◽  
Gene Promoters ◽  
Dna Hypermethylation ◽  
Tet Proteins ◽  
Tet Protein

Abstract Background: The Tet protein family (Tet1, Tet2, and Tet3) regulate DNA methylation through conversion of 5-methylcytosine to 5-hydroxymethylcytosine which can ultimately result in DNA demethylation and play a critical role during early mammalian development and pluripotency¬. While multiple groups have generated knockouts combining loss of different Tet proteins in murine embryonic stem cells (ESCs), differences in genetic background and approaches has made it difficult to directly compare results and discern the direct mechanism by which Tet proteins regulate the transcriptome. To address this concern, we utilized genomic editing in an isogenic pluripotent background which permitted a quantitative, flow-cytometry based measurement of pluripotency in combination with genome-wide assessment of gene expression and DNA methylation changes. Our ultimate goal was to generate a resource of large-scale datasets to permit hypothesis-generating experiments. Results: We demonstrate a quantitative disparity in the differentiation ability among Tet protein deletions, with Tet2 single knockout exhibiting the most severe defect, while loss of Tet1 ¬alone or combinations of Tet genes showed a quantitatively intermediate phenotype. Using a combination of transcriptomic and epigenomic approaches we demonstrate an increase in DNA hypermethylation and a divergence of transcriptional profiles in pluripotency among Tet deletions, with loss of Tet2 having the most profound effect in undifferentiated ESCs. Conclusions: We conclude that loss of Tet2 has the most dramatic effect both on the phenotype of ESCs and the transcriptome compared to other genotypes. While loss of Tet proteins increased DNA hypermethylation, especially in gene promoters, these changes in DNA methylation did not correlate with gene expression changes. Thus, while loss of different Tet proteins alters DNA methylation, this change does not appear to be directly responsible for transcriptome changes. Thus, loss of Tet proteins likely regulates the transcriptome epigenetically both through altering 5mC but also through additional mechanisms. Nonetheless, the transcriptome changes in pluripotent Tet2-/- ESCs compared to wild-type implies that the disparities in differentiation can be partially attributed to baseline alterations in gene expression.

scholarly journals Deletion of Tet proteins results in quantitative disparities during ESC differentiation partially attributable to differences in gene expression

2019 ◽  
Author(s):  
Michael J Reimer ◽  
Kirthi Pulakanti ◽  
Linzheng Shi ◽  
Alex Abel ◽  
Mingyu Liang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Critical Role ◽  
Embryonic Stem ◽  
Dna Demethylation ◽  
Intermediate Phenotype ◽  
Gene Promoters ◽  
Dna Hypermethylation ◽  
Tet Proteins ◽  
Tet Protein

Abstract Background: The Tet protein family (Tet1, Tet2, and Tet3) regulate DNA methylation through conversion of 5-methylcytosine to 5-hydroxymethylcytosine which can ultimately result in DNA demethylation and play a critical role during early mammalian development and pluripotency¬. While multiple groups have generated knockouts combining loss of different Tet proteins in murine embryonic stem cells (ESCs), differences in genetic background and approaches has made it difficult to directly compare results and discern the direct mechanism by which Tet proteins regulate the transcriptome. To address this concern, we utilized genomic editing in an isogenic pluripotent background which permitted a quantitative, flow-cytometry based measurement of pluripotency in combination with genome-wide assessment of gene expression and DNA methylation changes. Our ultimate goal was to generate a resource of large-scale datasets to permit hypothesis-generating experiments. Results: We demonstrate a quantitative disparity in the differentiation ability among Tet protein deletions, with Tet2 single knockout exhibiting the most severe defect, while loss of Tet1 ¬alone or combinations of Tet genes showed a quantitatively intermediate phenotype. Using a combination of transcriptomic and epigenomic approaches we demonstrate an increase in DNA hypermethylation and a divergence of transcriptional profiles in pluripotency among Tet deletions, with loss of Tet2 having the most profound effect in undifferentiated ESCs. Conclusions: We conclude that loss of Tet2 has the most dramatic effect both on the phenotype of ESCs and the transcriptome compared to other genotypes. While loss of Tet proteins increased DNA hypermethylation, especially in gene promoters, these changes in DNA methylation did not correlate with gene expression changes. Thus, while loss of different Tet proteins alters DNA methylation, this change does not appear to be directly responsible for transcriptome changes. Thus, loss of Tet proteins likely regulates the transcriptome epigenetically both through altering 5mC but also through additional mechanisms. Nonetheless, the transcriptome changes in pluripotent Tet2-/- ESCs compared to wild-type implies that the disparities in differentiation can be partially attributed to baseline alterations in gene expression.

scholarly journals Deletion of Tet proteins results in quantitative disparities during ESC differentiation partially attributable to alterations in gene expression

2019 ◽  
Author(s):  
Michael J Reimer ◽  
Kirthi Pulakanti ◽  
Linzheng Shi ◽  
Alex Abel ◽  
Mingyu Liang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Critical Role ◽  
Embryonic Stem ◽  
Dna Demethylation ◽  
Intermediate Phenotype ◽  
Gene Promoters ◽  
Dna Hypermethylation ◽  
Tet Proteins ◽  
Tet Protein

Abstract Background: The Tet protein family (Tet1, Tet2, and Tet3) regulate DNA methylation through conversion of 5-methylcytosine to 5-hydroxymethylcytosine which can ultimately result in DNA demethylation and play a critical role during early mammalian development and pluripotency¬. While multiple groups have generated knockouts combining loss of different Tet proteins in murine embryonic stem cells (ESCs), differences in genetic background and approaches has made it difficult to directly compare results and discern the direct mechanism by which Tet proteins regulate the transcriptome. To address this concern, we utilized genomic editing in an isogenic pluripotent background which permitted a quantitative, flow-cytometry based measurement of pluripotency in combination with genome-wide assessment of gene expression and DNA methylation changes. Our ultimate goal was to generate a resource of large-scale datasets to permit hypothesis-generating experiments. Results: We demonstrate a quantitative disparity in the differentiation ability among Tet protein deletions, with Tet2 single knockout exhibiting the most severe defect, while loss of Tet1 ¬alone or combinations of Tet genes showed a quantitatively intermediate phenotype. Using a combination of transcriptomic and epigenomic approaches we demonstrate an increase in DNA hypermethylation and a divergence of transcriptional profiles in pluripotency among Tet deletions, with loss of Tet2 having the most profound effect in undifferentiated ESCs. Conclusions: We conclude that loss of Tet2 has the most dramatic effect both on the phenotype of ESCs and the transcriptome compared to other genotypes. While loss of Tet proteins increased DNA hypermethylation, especially in gene promoters, these changes in DNA methylation did not correlate with gene expression changes. Thus, while loss of different Tet proteins alters DNA methylation, this change does not appear to be directly responsible for transcriptome changes. Thus, loss of Tet proteins likely regulates the transcriptome epigenetically both through altering 5mC but also through additional mechanisms. Nonetheless, the transcriptome changes in pluripotent Tet2-/- ESCs compared to wild-type implies that the disparities in differentiation can be partially attributed to baseline alterations in gene expression.

scholarly journals SETDB1 prevents TET2-dependent activation of IAP retroelements in naïve embryonic stem cells

2017 ◽  
Author(s):  
Özgen Deniz ◽  
Lorenzo de la Rica ◽  
Kevin C. L. Cheng ◽  
Dominik Spensberger ◽  
Miguel R. Branco
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Dna Demethylation ◽  
Endogenous Retroviruses ◽  
Preimplantation Embryos ◽  
Dependent Manner ◽  
Epigenetic Mechanisms

BackgroundEndogenous retroviruses (ERVs), which are responsible for 10% of spontaneous mouse mutations, are kept under control via several epigenetic mechanisms. The H3K9 histone methyltransferase SETDB1 is essential for ERV repression in embryonic stem cells (ESCs), with DNA methylation also playing an important role. It has been suggested that SETDB1 protects ERVs from TET- dependent DNA demethylation, but the relevance of this mechanism for ERV expression remains unclear. Moreover, previous studies have been performed in primed ESCs, which are not epigenetically or transcriptionally representative of preimplantation embryos.ResultsWe used naïve ESCs to investigate the role of SETDB1 in ERV regulation and, in particular, its relationship with TET-mediated DNA demethylation. Naïve ESCs show an increased dependency on SETDB1 for ERV silencing when compared to primed ESCs, including at the highly mutagenic intracisternal A particles (IAPs). We found that, in the absence of SETDB1, TET2 activates IAP elements in a catalytic-dependent manner. Surprisingly, however, TET2 does not drive changes in DNA methylation levels at IAPs, suggesting that it regulates these transposons indirectly. Instead, SETDB1 depletion leads to a TET2-dependent loss of H4R3me2s, which is indispensable for IAP silencing during epigenetic reprogramming.ConclusionsOur results demonstrate a novel and unexpected role for SETDB1 in protecting IAPs from TET2-dependent histone arginine demethylation.

scholarly journals DNA methylation on N6-adenine in mammalian embryonic stem cells

Nature ◽  
2016 ◽  
Vol 532 (7599) ◽  
pp. 329-333 ◽  
Author(s):  
Tao P. Wu ◽  
Tao Wang ◽  
Matthew G. Seetin ◽  
Yongquan Lai ◽  
Shijia Zhu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Embryonic Stem

scholarly journals Corrigendum: p53 is essential for DNA methylation homeostasis in naïve embryonic stem cells, and its loss promotes clonal heterogeneity

2018 ◽  
Vol 32 (19-20) ◽  
pp. 1358-1358
Author(s):  
Ayala Tovy ◽  
Adam Spiro ◽  
Ryan McCarthy ◽  
Zohar Shipony ◽  
Yael Aylon ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Clonal Heterogeneity

Dysregulation of schizophrenia-associated genes and genome-wide hypomethylation in neurons overexpressing DNMT1

Epigenomics ◽  
2021 ◽  
Author(s):  
Sonal Saxena ◽  
Sumana Choudhury ◽  
Pranay Amruth Maroju ◽  
Anuhya Anne ◽  
Lov Kumar ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Copy Number ◽  
Embryonic Stem ◽  
Wild Type ◽  
Independent Manner ◽  
Transcript Levels ◽  
Genome Wide ◽  
Methylation Patterns ◽  
Increased Activity

Aim: To study the effects of DNMT1 overexpression on transcript levels of genes dysregulated in schizophrenia and on genome-wide methylation patterns. Materials & methods: Transcriptome and DNA methylome comparisons were made between R1 (wild-type) and Dnmt1tet/tet mouse embryonic stem cells and neurons overexpressing DNMT1. Genes dysregulated in both Dnmt1tet/tet cells and schizophrenia patients were studied further. Results & conclusions: About 50% of dysregulated genes in patients also showed altered transcript levels in Tet/Tet neurons in a DNA methylation-independent manner. These neurons unexpectedly showed genome-wide hypomethylation, increased transcript levels of Tet1 and Apobec 1-3 genes and increased activity and copy number of LINE-1 elements. The observed similarities between Tet/Tet neurons and schizophrenia brain samples reinforce DNMT1 overexpression as a risk factor.

scholarly journals Effects of a hypomagnetic field on DNA methylation during the differentiation of embryonic stem cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Soonbong Baek ◽  
Hwan Choi ◽  
Hanseul Park ◽  
Byunguk Cho ◽  
Siyoung Kim ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Hypomagnetic Field
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